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    Research Update 540

    The latest research highlights for 6 June 2022.


    Development of subretinal hemorrhage after treatment discontinuation for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

    Graefes Archives if Clinical and Experimental Ophthalmology 2022 May 25

    Kim JH, Kim JW, Kim CG.

    Purpose: To investigate the incidence, risk factors, and their influence on visual outcomes of subretinal hemorrhage (SRH) in patients with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy(PCV) who discontinue treatment.

    Methods: This retrospective study included 148 patients with nAMD and PCV who discontinued treatment. The development of a 3-disc area or greater extent of SRH after treatment discontinuation was identified. Visual acuity at the final visit was compared between patients with and those without SRH. Factors associated with SRH were then analyzed.

    Results: During the mean 56.8 ± 18.2 months of follow-up, treatment was discontinued at a mean 24.1 ± 16.3 months after diagnosis. SRH developed in 24 (16.2%) patients at a mean 21.5 ± 17.6 months after treatment discontinuation. The visual acuity at the final follow-up was significantly worse in patients with SRH than in those without SRH (P < 0.001). There was a significant difference in the incidence of SRH among the different types of macular neovascularization (MNV) (P = 0.024). In particular, the incidence of type 3 MNV was relatively high (36.0%).

    Conclusions: The development of SRH may lead to very poor visual prognosis in patients who discontinue treatment. The high risk of SRH in type 3 MNV suggests the need for caution when choosing treatment discontinuation in cases of type 3 MNV.

    DOI: 10.1007/s00417-022-05702-w


    Osteoarthritis Is Associated With an Increased Risk of Age-Related Macular Degeneration: A Population-Based Longitudinal Follow-Up Study.

    Frontiers in Medicine (Lausanne) 2022 May 10.

    Chiu YH, Huang JY, Huang YP, Pan SL.

    Aims: To investigate the long-term risk of age-related macular degeneration (AMD) in persons with osteoarthritis (OA).

    Methods: This retrospective cohort study first enrolled 71,609 subjects diagnosed with OA, and 236,169 without such a diagnosis between January 1, 2002 and December 31, 2005, from the Longitudinal Health Insurance Database 2005. All were aged 40-69. After excluding subjects who had pre-existing AMD and/or who had missing socioeconomic data, frequency matching by sex and age was performed. This resulted in there being 60,274 subjects in each of the final matched OA and non-OA groups. The study participants were followed up to the occurrence of AMD, death, or the end of 2011. We used Cox proportional-hazards regression to estimate the impact of OA on the risk of developing AMD, and performed subgroup analyses stratified by sex and age.

    Results: The median follow-up time was 8.9 years, with an interquartile range of 1.4 years. The incidence rate of AMD in the OA group was 2.77 per 1,000 person-years [95% confidence interval (CI), 2.62-2.92], and in the non-OA group, 2.06 per 1,000 person-years (95% CI, 1.94-2.19). The adjusted hazard ratio (HR) of AMD for the OA group was therefore 1.30 (95% CI, 1.20-1.41). In the subgroup analysis stratified by sex for the OA group, the adjusted HRs of AMD were 1.29 in the women’s stratum and 1.31 in the men’s. When stratified by age, the adjusted HRs of AMD for the younger (40-54 years) and older (55-69 years) strata were 1.28 and 1.31, respectively.

    Conclusions: Persons with OA have an increased risk of developing AMD, regardless of age and sex.

    DOI: 10.3389/fmed.2022.854629

    Relative Telomere Length Is Associated With Age-Related Macular Degeneration in Women.

    Investigative Ophthalmology and Vision Science 2022 May 2.

    Koller A, Brandl C, Lamina C, Zimmermann ME, Summerer M, Stark KJ, Würzner R, Heid IM, Kronenberg F.

    Purpose: Relative telomere length (RTL) is a biomarker for physiological aging. Premature shortening of telomeres is associated with oxidative stress, which is one possible pathway that might contribute to age-related macular degeneration (AMD). We therefore aimed to investigate the association between RTL and AMD in a well-characterized group of elderly individuals.

    Methods: We measured RTL in participants of the AugUR study using a multiplex quantitative PCR-based assay determining the ratio between the telomere product and a single-copy gene product (T/S ratio). AMD was assessed by manual grading of color fundus images using the Three Continent AMD Consortium Severity Scale.

    Results: Among the 2262 individuals 70 to 95 years old (627 with AMD and 1635 without AMD), RTL was significantly shorter in individuals with AMD compared to AMD-free participants. In age- and sex-adjusted logistic regression analyses, we observed an 8% higher odds for AMD per 0.1 unit shorter RTL (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.02-1.14; P = 0.005). The estimates remained stable when adjusted for smoking, high-density lipoprotein cholesterol, cardiovascular disease, diabetes, and hypertension. Interestingly, this association was only present in women (OR = 1.14; 95% CI, 1.06-1.23; P < 0.001), but not in men (OR = 1.01; 95% CI, 0.93-1.10; P = 0.76). A significant sex-by-RTL interaction on AMD was detected (P = 0.043).

    Conclusions: Our results show an association of RTL with AMD that was restricted to women. This is in line with altered reactive oxygen species levels and higher telomerase activity in women and provides an indication for a sex-differential pathway for oxidative stress and AMD.

    DOI: 10.1167/iovs.63.5.30


    High-Density Optical Coherence Tomography Analysis Provides Insights Into Early/Intermediate Age-Related Macular Degeneration Retinal Layer Changes.

    Investigative Ophthalmology and Vision Science 2022 May 2.

    Trinh M, Kalloniatis M, Alonso-Caneiro D, Nivison-Smith L.

    Purpose: To topographically map all of the thickness differences in individual retinal layers between early/intermediate age-related macular degeneration (AMDearly/AMDint) and normal eyes and to determine interlayer relationships.

    Methods: Ninety-six AMDtotal (48 AMDearly and 48 AMDint) and 96 normal eyes from 192 participants were propensity-score matched by age, sex, and refraction. Retrospective optical coherence tomography (OCT) macular cube scans were acquired, and high-density (60 × 60 0.01-mm2) grid thicknesses were custom extracted for comparison between AMDtotal and normal eyes corrected for confounding. Resultant “normal differences” underwent cluster, interlayer correlation, and dose-response analyses for the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer + Henle’s fiber layer (ONL+HFL), inner and outer segment (IS/OS) thickness, and retinal pigment epithelium (RPE) to Bruch’s membrane (BM) thickness.

    Results: AMDtotal inner retinal clusters demonstrated extensively thinned RNFL, GCL, IPL, and paracentral INL and thickened INL elsewhere, with normal difference means ranging from -8.13 µm (95% confidence interval [CI], -11.12 to -5.13) to 1.58 µm (95% CI, 1.07-2.09) (P < 0.0001 to P < 0.05). Outer retinal clusters displayed thinned paracentral OPL/ONL+HFL, central IS/OS, and peripheral RPE-BM and thickened central RPE-BM, with means ranging from -1.31 µm (95% CI, -2.06 to -0.55) to 2.99 µm (95% CI, 0.97-5.01] (P < 0.0001 to P <0.05). Effect sizes (-2.56 to 9.93 SD), cluster sizes, and eccentricity effects varied. All interlayer correlations were negligible to moderate regardless of AMD severity. Only the RPE-BM was partly thicker with greater AMD severity (up to 5.44 µm; 95% CI, 4.88-6.00; P < 0.01).

    Conclusions: From the early stage, AMD eyes demonstrate thickness differences compared to normal with unique topographies across all retinal layers. Poor interlayer correlations highlight that the outer retina inadequately reflects complete retinal health. The clinical importance of OCT assessment across all individual retinal layers in early/intermediate AMD requires further investigation.

    DOI: 10.1167/iovs.63.5.36


    Analyzing subgroups and treatment discontinuation in a Finnish cohort of patients with neovascular AMD.

    Ophthalmologica 2022 May 25.

    Ollila T, Silvennoinen J, Joshi A, Liu J, Kulathinal S, Immonen I.

    Purpose To study the regional detailed visual outcome and treatment discontinuation of neovascular age-related macular degeneration (nAMD).

    Methods Clinical records of 110 patients treated for nAMD at the sole referral center in the Helsinki region were analysed retrospectively. The follow-up was up to the fourth year.

    Results The mean visual acuity (VA) at baseline was 56.3 (SD 16.2) letters. The mean last VA at the first year was 59.7 (20.2), and the corresponding values for the second, third and fourth years were 60.8 (20.6), 60.0 (19.0) and 59.7 (19.3). The mean difference from baseline was +3.39 (SD 14.6), +3.59 (17.6), +0.08 (18.9) and +3.08 (14.3). The number of patients declined each year, with only 51 % of the patients being in treatment until the fourth year. The patients with shorter duration of follow-up tended to have a lower baseline VA, lesser gains and an earlier decline in VA. The VA levels at the last visit were poorer in the shorter follow group. The initial VA response predicted later VA, whereas VA at baseline, age or sex had no effect. However, the effect vanished with a longer time in treatment.

    Conclusions Long-term VA stabilization was obtained in a regional material. Patients with neovascular AMD consists of cohorts with varying visual outcome and treatment time. Many of the patients benefit from the treatment for some time, however. When comparing real-world results, the outcome of the different follow-up time cohorts should be considered. This calls for new methods for analysing real world nAMD treatment results. Key words: neovascular age-related macular degeneration, anti-VEGF treatment, visual acuity, real-world studies.

    DOI: 10.1159/000524848

    Efficacy and safety of brolucizumab versus aflibercept in eyes with early persistent retinal fluid: 96-week outcomes from the HAWK and HARRIER studies.

    Eye (London) 2022 May 21.

    Lally DR, Loewenstein A, Arnold JJ, Yang YC, Gedif K, Best C, Patel H, Tadayoni R, Heier JS.

    Objective: Post-hoc analysis to compare the outcomes of brolucizumab 6 mg vs. aflibercept 2 mg in neovascular age-related macular degeneration (nAMD) patients with early persistent retinal fluid in HAWK and HARRIER.

    Methods: After 3 monthly loading doses, brolucizumab-treated eyes (N = 730) received injections every 12 weeks (q12w) or q8w if disease activity was detected. Aflibercept-treated eyes (N = 729) received fixed q8w dosing. Early persistent fluid was defined as the presence of subretinal fluid and/or intraretinal fluid up to Week 12.

    Results: A lower proportion of brolucizumab patients had early persistent retinal fluid compared with aflibercept (11.2% (n = 82) vs. 19.2% (n = 140)). In these patients, 34.1% of the brolucizumab-treated group achieved a ≥ 15 ETDRS letter gain in best corrected visual acuity (BCVA) from baseline at Week 96 compared with 20.7% of the aflibercept-treated group. Brolucizumab achieved numerically better BCVA outcomes (Week 96: brolucizumab, +6.4 letters; aflibercept, +3.7 letters) and significantly greater central subfield thickness reductions versus aflibercept from baseline through Week 96 (Week 96: -202 µm vs. -145 µm; p = 0.0206). Brolucizumab demonstrated an overall favourable benefit/risk profile in this patient cohort. In their unmasked, post-hoc review, the Safety Review Committee identified two cases of retinal vasculitis and no cases of retinal vascular occlusion in the brolucizumab arm; no cases of retinal vasculitis or retinal vascular occlusion were identified in the aflibercept arm.

    Conclusion: In this analysis, anatomical and visual outcomes were better with brolucizumab compared with aflibercept. Brolucizumab may therefore achieve greater disease control than aflibercept in nAMD patients with early persistent retinal fluid.

    DOI: 10.1038/s41433-022-02092-5


    Pathophysiology of Age-Related Macular Degeneration. Implications for Treatment.

    Ophthalmic Research 2022 May 25.

    Garcia-Garcia J, Usategui-Martin R, Sanabria MR, Fernandez-Perez E, Telleria JJ, Coco-Martin RM.

    Age-related macular degeneration (AMD) is a complex, multifactorial, progressive retinal disease that affects millions of people worldwide and has become the leading cause of visual impairment in developed countries. The disease etiopathogenesis is not understood fully, although many triggers and processes that lead to dysfunction and degeneration of the retinal pigment epithelium (RPE) already have been identified. Thus, the lack of cellular control of oxidative stress, altered proteostasis, dysfunction of lipid homeostasis, and mitochondrial dysfunction form an internal feedback loop that causes the RPE to fail and allows accumulation of abnormal misfolded proteins and abnormal lipids that will form drusen. An inadequate antioxidant response, deficits in autophagy mechanisms, and dysregulation of the extracellular matrix (ECM) help to increase the deposition of abnormal drusen material over time. The drusen then act as inflammatory centers that trigger chronic inflammation of the subretinal space in which microglia and recruited macrophages also are involved, and the complement system is a key component. Choriocapillaris degeneration and nutritional influences are also classic elements recognized in the AMD pathophysiology. The genetic component of the disease is embodied in the recognition of the described risk or protective polymorphisms of some complement (mainly complement factor H, CFH) and ECM related genes (mainly age-related maculopathy susceptibility 2/high-temperature requirement protein A1, ARMS2/HTRA1). Carriers of the risk haplotype at ARMS2/HTRA1 have a higher risk of developing late AMD at a younger age. Finally, gut microbiota and epigenetics may play a role in modulating the progression to advanced AMD with the presence of local inflammatory conditions. Because of multiple implicated processes, different complex combinations of treatments will probably be the best option to obtain the best visual results; they in turn will differ depending on the type and spectrum of disease affecting individual patients or the disease stage in each patient at a specific moment. This will undoubtedly lead to personalized medicine for control and hopefully a future cure, which necessitates the continued unraveling of all the processes involved in the pathogenesis of AMD that must be understood to devise the combinations of treatments for different concurrent or subsequent problems.

    DOI: 10.1159/000524942

    Molecular Mechanisms Underlying the Therapeutic Role of Vitamin E in Age-Related Macular Degeneration.

    Frontiers Neuroscience 2022 May 4.

    Edwards G, Olson CG, Euritt CP, Koulen P.

    The eye is particularly susceptible to oxidative stress and disruption of the delicate balance between oxygen-derived free radicals and antioxidants leading to many degenerative diseases. Attention has been called to all isoforms of vitamin E, with α-tocopherol being the most common form. Though similar in structure, each is diverse in antioxidant activity. Preclinical reports highlight vitamin E’s influence on cell physiology and survival through several signaling pathways by activating kinases and transcription factors relevant for uptake, transport, metabolism, and cellular action to promote neuroprotective effects. In the clinical setting, population-based studies on vitamin E supplementation have been inconsistent at times and follow-up studies are needed. Nonetheless, vitamin E’s health benefits outweigh the controversies. The goal of this review is to recognize the importance of vitamin E’s role in guarding against gradual central vision loss observed in age-related macular degeneration (AMD). The therapeutic role and molecular mechanisms of vitamin E’s function in the retina, clinical implications, and possible toxicity are collectively described in the present review.

    DOI: 10.3389/fnins.2022.890021


    Choroidal Effusion following Intravitreal Brolucizumab Injection: A Case Report.

    Case Reports in Ophthalmology 2022 Mar 17.

    Sim HE, Kim JS, Hwang JH.

    This report describes a case of choroidal effusion after intravitreal brolucizumab injection for wet age-related macular degeneration (AMD). A 71-year-old Korean man with a history of wet AMD visited our clinic. On examination, the best-corrected distance visual acuity (BCVA) was 20/200 in the right eye. Fundus photography and optical coherence tomography showed wet AMD in the right eye. The patient showed no improvement while undergoing treatment with anti-vascular endothelial growth factor therapy (aflibercept, 6 times; ranibizumab, 5 times; and bevacizumab 3 times). We administered intravitreal brolucizumab injections in the right eye of the patient. After first brolucizumab injection, the BCVA improved from 20/200 to 20/63 in the right eye. Two months after the intravitreal brolucizumab injection, recurrence of wet AMD and deterioration of the BCVA to 20/200 was observed on the right eye. The patient underwent a second intravitreal brolucizumab injection in the right eye in the same manner. Three days after the second brolucizumab injection, choroidal effusion was observed in the right eye. The choroidal effusion resolved completely 12 days after the injection, without any additional treatment. Intravitreal brolucizumab injection may provoke choroidal effusion. Although it may resolve promptly, short-term follow-up fundus examinations may be necessary for the early diagnosis and treatment of this complication.

    DOI: 10.1159/000522531

    Macular Hole Formation Following Intravitreal Aflibercept for Neovascular Age-Related Macular Degeneration.

    Case Reports in Ophthalmology 2022 Apr 4.

    Ali Said Y, Vanwynsberghe D, Jacob J.

    This case report describes full-thickness macular hole formation after intravitreal aflibercept injections for the treatment of macular neovascularization in neovascular age-related macular degeneration (AMD). Only limited case reports and case series have reported this possible adverse event after aflibercept injection. Possible mechanisms leading to the formation of a macular hole subsequent to intravitreal injection are focal tractional forces on the vitreoretinal interface due to globe deformation during needle insertion, vitreous syneresis, and vitreous incarceration at the injection site, and tangential shearing forces on the posterior surface of the retina due to contraction and rapid volume reduction of the neovascular membrane or a decrease in intra- or subretinal fluid. Furthermore, some reports suggest a toxic effect of the anti-vascular endothelial growth factor agent on a previously compromised retina as etiological factor. Macular hole formation may thus represent a rare adverse event of intravitreal aflibercept injection in patients with neovascular AMD, and it should be included in the differential diagnosis of post-injectional visual loss.

    DOI: 10.1159/000521975

    Prevalence of diabetic retinopathy in women with pregestational diabetes during pregnancy and the postpartum.

    Clinical & Experimental Ophthalmology. 2022 May 23.

    Widyaputri F, Rogers SL, Khong EWC, Nankervis AJ, Conn JJ, Sasongko MB, Shub A, Fagan XJ, Guest D, Symons RCA, Lim LL.

    Background: Diabetic retinopathy (DR) may be affected by pregnancy. The majority of prevalence data regarding DR in pregnancy predate the advent of contemporary guidelines for diabetes management during pregnancy. This study reports DR prevalence and associated risk factors in women with pregestational diabetes during pregnancy and the postpartum in Australia.

    Methods: A total of 172 pregnant women with type 1 (T1DM) or type 2 diabetes diagnosed pre-pregnancy were prospectively recruited from two obstetrics hospitals in Melbourne (November 2017 – March 2020). Eye examinations were scheduled in each trimester, at 3-months, 6-months, and 12-months postpartum. DR severity was graded from 2-field fundus photographs by an independent grader utilising the Airlie House Classification. Sight-threatening DR (STDR) was defined as the presence of diabetic macular oedema or proliferative DR.

    Results: Overall, 146 (84.9%) women had at least one eye examination during pregnancy. The mean age was 33.8 years (range 19-51), median diabetes duration was 7.0 years (IQR 3.0-17.0), 71 women (48.6%) had T1DM. DR and STDR prevalence during pregnancy per 100 eyes was 24.3 (95%CI 19.7-29.6) and 9.0 (95%CI 6.1-12.9); while prevalence in the postpartum was 22.2 (95%CI 16.5-29.3) and 10.0 (95%CI 5.4-17.9), respectively. T1DM, longer diabetes duration, higher HbA1c in early pregnancy, and pre-existing nephropathy were significant risk factors.

    Conclusions: The prevalence of DR in pregnant women was similar to the non-pregnant diabetic population in Australia. One in 9 participants had STDR during pregnancy and the postpartum, highlighting the need to optimise DR management guidelines in pregnancy given the significant risk of vision loss. This article is protected by copyright. All rights reserved.

    DOI: 10.1111/ceo.14111


    Developing and validating a multivariable prediction model which predicts progression of intermediate to late age-related macular degeneration-the PINNACLE trial protocol.

    Eye (London) 2022 May 25.

    Aims: Age-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD.

    Methods: The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55-90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models.

    Conclusions: This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.

    DOI: 10.1038/s41433-022-02097-0