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    Research update: 507

    The latest research highlights for 23 August 2021

    DRUG TREATMENT

    Intraocular pressure decreases in eyes with glaucoma-related diagnoses after conversion to aflibercept for treatment-resistant age-related macular degeneration.

    Eye (Lond). 2021 Aug 12.

    Ramsey DJ, McCullum JC, Steinberger EE, Zhang Y, Alwreikat AM, Cooper ML, Roh S, Cotran PR.

    OBJECTIVE: To understand intraocular pressure (IOP) response after switching from intravitreal bevacizumab (IVB) and/or ranibizumab (IVR) to intravitreal aflibercept (IVA) for treatment-resistant neovascular age-related macular degeneration (nAMD) in patients with and without coexisting glaucoma-related diagnoses.

    METHODS: Retrospective, cross-sectional comparative case series of 62 eyes of 58 patients treated with intravitreal injection for nAMD from March 2010 to April 2018. Patients with glaucoma-related diagnoses, defined here as open-angle glaucoma or suspicion of open-angle glaucoma, ocular hypertension, and/or narrow-angle glaucoma, were compared to those without glaucoma. IOP data were collected at baseline, at the three visits where patients received loading doses of IVB/IVR, and at all of the visits following the switch to IVA through the end of follow-up.

    RESULTS: 19 eyes with pre-existing glaucoma-related diagnoses were compared to 43 eyes without such diagnoses. Baseline IOP was similar for glaucoma and non-glaucoma patients. The loading doses of IVB/IVR did not impact IOP; however, a small, sustained rise in IOP was noted among patients with glaucoma-related diagnoses by the final IVB/IVR injections before the switch to IVA (∆IOP 1.61 ± 0.52 mmHg, P < 0.002). After conversion to IVA, pre-injection IOP declined in eyes both with (-1.59 ± 0.54 mmHg, P < 0.001) and without (-0.99 ± 0.28 mmHg, P < 0.001) glaucoma-related diagnoses.

    CONCLUSIONS: IOP in patients with glaucoma-related diagnoses appears to be more sensitive to intravitreal injections than it is in patients without glaucoma-related diagnoses. It rises with IVB/IVR and declines after the switch to IVA. Switching patients with nAMD to IVA may present an opportunity to lower IOP in patients with glaucoma.

    DOI: 10.1038/s41433-021-01729-1

    Analyses of the effects of persistent subretinal fluid on visual/anatomic outcomes according to the type of macular neovascularization during the relaxed treat-and-extend protocol in age-related macular degeneration patients.

    BMC Ophthalmol. 2021 Aug 10;21(1):294.

    Kim KT, Chae JB, Lee S, Seo EJ, Kim DY.

    BACKGROUND: To analyze the long-term effects of persistent subretinal fluid (SRF) on visual/anatomic outcomes according to the type of macular neovascularization (MNV) during relaxed treat-and-extend regimen with anti-vascular endothelial growth factor (anti-VEGF) agents in age-related macular degeneration (AMD) patients.

    METHODS: Patients with fovea-involving type 1 or type 2 MNV, treated with a relaxed treat-and-extend regimen for 2 years were retrospectively reviewed. Eyes with SRF observed more than three times per year were defined as the ‘persistent SRF (+) group’. To exclude the effects of IRF as much as possible, the eyes with persistent IRF were excluded. The effects of persistent SRF on the best-corrected visual acuity (BCVA), central subfield retinal thickness (CST), and changes in the photoreceptor layer (PRL) thickness and outer retinal bands (external limiting membrane, ellipsoid zone, and cone outer segment tip line) after anti-VEGF injection were analyzed for each MNV type.

    RESULTS: Seventy-seven eyes with type 1 MNV (44 eyes with persistent SRF) and 53 eyes with type 2 MNV (18 eyes with persistent SRF) were enrolled. Following a relaxed treat-and-extend regimen with anti-VEGF agents, BCVA and CST improved for each MNV type. In comparison between persistent SRF (+) and persistent SRF (-) group, there were no differences in the amount of change in BCVA and CST between the two groups for each MNV type during 2-year follow-up periods. In addition, there were no differences in the amount of reduction in PRL thickness and state of the outer retinal bands between the two groups for each MNV type.

    CONCLUSIONS: Using a relaxed treat-and-extend regimen with anti-VEGF agents, persistent SRF did not have additional effects on visual and anatomic outcomes by 2 years, regardless of the MNV type.

    DOI: 10.1186/s12886-021-02063-6

    The Effect of Treatment Discontinuation During the COVID-19 Pandemic on Visual Acuity in Exudative Neovascular Age-Related Macular Degeneration: 1-Year Results.

    Ophthalmol Ther. 2021 Aug 9:1-11.

    Stattin M, Ahmed D, Graf A, Haas AM, Kickinger S, Jacob M, Krepler K, Ansari-Shahrezaei S.

    INTRODUCTION: To evaluate the effect of a 9-week treatment deferral due to healthcare restrictions caused by Austria’s first governmental lockdown associated with the coronavirus disease 2019 (COVID-19) pandemic on visual acuity (VA) in eyes compromised by exudative neovascular age-related macular degeneration (nAMD) after 1 year.

    METHODS: Retrospective data collection of 98 eyes (98 patients) with a treatment discontinuation at a tertiary eye care center (Clinic Landstraße, Vienna Healthcare Group, Austria) between March 16 and May 4, 2020. Prior to the lockdown, patients received multiple intravitreal injections (IVI) of anti-vascular endothelial growth factor with a personalized treatment interval for 3 years on average and at least three IVI after the lockdown.

    RESULTS: When the treatment interval doubled to 117.6 ± 31.4 days in spring 2020, patients lost 2.2 ± 4.6 ETDRS letters (p = 0.002) on average before reinitiating therapy. In total, 4.1 ± 8.1 letters (p < 0.0001) were lost despite continuous individual re-treatment over the course of the next year. In a univariate analysis, the extended interval time remained statistically significant (p < 0.0001), indicating a larger VA reduction within intervals with increasing interval time in days.

    CONCLUSION: The short-term treatment interruption had a persistent negative impact on the VA course of eyes under therapy after 1 year. Continuous therapy independent of the underlying treatment regimen remains of utmost importance in exudative nAMD. Our data should create awareness to regulators regarding future decisions despite the global pandemic.

    Plain Language Summary: Age-related macular degeneration (AMD) is the leading cause of legal blindness in developed countries. Wet AMD refers to the existence of new vessel growth in the macular, the part of the retina with the highest concentration of photoreceptors and hence the best visual acuity. The gold standard therapy of wet AMD consists of repeated injections of an antibody against new vessel formation into the eye to stabilize the disease. The sudden break of a treatment regimen for an individual person has never been investigated as it is ethically not acceptable. The coronavirus disease 2019 (COVID-19) pandemic and its associated lockdown led to an emerging situation in spring, 2020. We were forced by governmental restrictions to minimize contact with the most vulnerable patient cohort—the elderly. As an initial consequence, the Medical Retina Unit of Department of Ophthalmology (Clinic Landstraße, Vienna Healthcare Group, Austria) postponed appointments of patients with only one eye afflicted by wet AMD. This study examined the effect of a short-term treatment deferral caused by the first national COVID-19 lockdown in eyes of patients with ongoing therapy of wet AMD in Austria. The break led to a persistent visual loss despite re-treatment, which was still evident after 1 year. Our findings provide further support for an adequate and permanent therapy of wet AMD and regard intravitreal injections as urgent standard of care. It should be taken into consideration by authorities in future pandemic planning.

    DOI: 10.1007/s40123-021-00381-y

    Follow-up rates for patients needing regular intravitreal therapy in rural north-western Western Australia.

    Rural Remote Health. 2021 Aug;21(3):6001.

    Nguyen AAK, Turner A.

    INTRODUCTION: Regular intravitreal injections are an important treatment for significant vision impairment caused by diabetic macular oedema. Barriers to intravitreal treatment for rural Australian patients include travel time to appointments, especially as patients face a high volume of other medical appointments for their diabetes and related co-morbidities. This audit addresses intravitreal injection compliance by identifying patients lost to follow up in north-western Western Australia.

    METHODS: A retrospective audit of all injections was performed in the Pilbara and Kimberley between January and December 2018. Outcome measures included total injections, number of injection patients, rates of patients lost to follow-up by region, Aboriginal and Torres Strait Islander status and diagnosis. The audit was extended to include the first 6 months of 2019 to ensure further treatment plan timeframes had lapsed.

    RESULTS: A total of 140 patients received injections, resulting in 346 injections. Ten patients were excluded due to relocation to another region and three patients were deceased. Seventeen patients were lost to follow-up (12.1%). Of those lost to follow-up, 14.3% were in the Pilbara region and 10% in the Kimberley region. Similar rates with respect to Indigenous status with 12.6% identifying as Aboriginal and 11.4% not. 15.8% were treated for diabetic macular oedema and 3.8% for age-related macular degeneration.

    CONCLUSION: The logistics of providing appropriate intravitreal therapy, including scheduling timely visits and working in hospital and community-controlled settings, requires a specific focus on those needing intravitreal treatment. The study highlights the importance of coordination and systems to enable patients to receive injections in remote settings. Further analysis of optimal patient management plans for appropriate frequency and treatment outcomes is required.

    DOI: 10.22605/RRH6001

    DIAGNOSIS & IMAGING

    Does real-time artificial intelligence-based visual pathology enhancement of three-dimensional optical coherence tomography scans optimise treatment decision in patients with nAMD? Rationale and design of the RAZORBILL study.

    Br J Ophthalmol. 2021 Aug 6:bjophthalmol-2021-319211.

    Holz FG, Abreu-Gonzalez R, Bandello F, Duval R, O’Toole L, Pauleikhoff D, Staurenghi G, Wolf A, Lorand D, Clemens A, Gmeiner B.

    BACKGROUND/RATIONALE: Artificial intelligence (AI)-based clinical decision support tools, being developed across multiple fields in medicine, need to be evaluated for their impact on the treatment and outcomes of patients as well as optimisation of the clinical workflow. The RAZORBILL study will investigate the impact of advanced AI segmentation algorithms on the disease activity assessment in patients with neovascular age-related macular degeneration (nAMD) by enriching three-dimensional (3D) retinal optical coherence tomography (OCT) scans with automated fluid and layer quantification measurements.

    METHODS: RAZORBILL is an observational, multicentre, multinational, open-label study, comprising two phases: (a) clinical data collection (phase I): an observational study design, which enforces neither strict visit schedule nor mandated treatment regimen was chosen as an appropriate design to collect data in a real-world clinical setting to enable evaluation in phase II and (b) OCT enrichment analysis (phase II): de-identified 3D OCT scans will be evaluated for disease activity. Within this evaluation, investigators will review the scans once enriched with segmentation results (i.e., highlighted and quantified pathological fluid volumes) and once in its original (i.e., non-enriched) state. This review will be performed using an integrated crossover design, where investigators are used as their own controls allowing the analysis to account for differences in expertise and individual disease activity definitions.

    CONCLUSIONS: In order to apply novel AI tools to routine clinical care, their benefit as well as operational feasibility need to be carefully investigated. RAZORBILL will inform on the value of AI-based clinical decision support tools. It will clarify if these can be implemented in clinical treatment of patients with nAMD and whether it allows for optimisation of individualised treatment in routine clinical care.

    DOI: 10.1136/bjophthalmol-2021-319211

    A comparative study of type 1 neovascularization: Neovascular age-related macular degeneration versus pachychoroid neovasculopathy.

    Eur J Ophthalmol. 2021 Aug 10:11206721211037828.

    Altinisik M, Kurt E, Sonmezer P, Kayikcioglu O, Ilker SS.

    PURPOSE: This study aimed to compare type 1 choroidal neovascularization (CNV) characteristics in eyes with pachychoroid neovasculopathy (PNV) and neovascular age-related macular degeneration (nAMD) using optical coherence tomography angiography (OCTA).

    METHODS: Treatment naive 23 eyes of 23 patients with PNV and 24 eyes of 24 patients with nAMD were evaluated. The height of pigment epithelial detachment (PED) and the central macular thickness were determined. OCTA sensitivity, CNV area, morphological patterns, and retinal superficial capillary plexus vessel density (SCP-VD) values were compared. The frequency of quiescent CNV, subretinal hyperreflective exudation (SHE), subretinal/intraretinal fluid, serous PED, double-layer sign (DLS), and pachyvessels were noted.

    RESULTS: CNV was detected on OCTA in 83.3% of nAMD eyes and 91.3% of PNV eyes (p = 0.66). Indistinct pattern was more common (74% vs 50%) and the CNV area (mm2) was smaller in PNV (0.77 ± 0.54 vs 1.57 ± 1.43) but did not reach significant levels (p = 0.27 and 0.33 respectively). SCP-VD was similar between the groups (p = 0.38). Statistically significant differences were found between groups in age and subfoveal choroidal thickness (p < 0.05). DLS and pachyvessels were found to be more frequently in PNV (p < 0.05). However, both groups had similar rates of quiescent CNV, SHE, subretinal/intraretinal fluid, and serous PED (p > 0.05).

    CONCLUSION: Morphological features, area, and activation findings of type 1 CNV may play a limited role in differentiating nAMD and PNV cases.

    DOI: 10.1177/11206721211037828

    Ocular Surface Temperature Differences in Retinal Vascular Diseases

    Retina. 2021 Aug 2.

    Naidorf H, Prat DL, Moisseiev J, Alhalel A, Huna-Baron R, Skaat A, Pilus S, Levi L, Leshno A.

    PURPOSE: To define the effect of age-related macular degeneration (AMD) and diabetic retinopathy (DR) on the ocular thermographic profile.

    METHODS: This retrospective cross-sectional study included subjects diagnosed with DR or AMD between January and April 2019. Individuals without ocular disease served as controls. Thermal imaging camera was used for ocular surface temperature (OST) acquisition. The mean temperatures of the medial cantus, lateral cantus, and cornea were calculated. RESULTS: Thermographic images were obtained from 133 subjects (260 eyes, 97 DR, 163 AMD) and 48 controls (55 eyes). OST was higher among AMD patients and lowest among DR patients (P < 0.001). A subgroup analysis revealed that eyes with diabetic macular edema (DME) had significantly higher OSTs than DR eyes without DME. Moreover, the OST in eyes with DME was similar to the measurements of the AMD group. There were no differences in OSTs between neovascular and non-neovascular AMD eyes.

    CONCLUSIONS: Although AMD and DR are considered posterior segment conditions, their effect on OST implies that the entire globe is involved. While both conditions result from similar multifactorial pathophysiologic changes, the differences in OST between DR and AMD might be due to dissimilarity in the balance of pathologic processes involved in each condition. Further research is required to better understand the pathophysiology of these diseases and their effect on OST as well as determine the effect of vasculature, circulation and tissue metabolism on ocular temperature.

    DOI: 10.1097/IAE.0000000000003278

    Visualising the choriocapillaris: Histology, imaging modalities and clinical research.

    Clin Exp Ophthalmol. 2021 Aug 12.

    Ng DS, Chan LK, Ng CM, Lai TYY.

    The choriocapillaris plays a considerable role in the normal physiology of the eye as well as in various diseases. Assessing the changes in the choriocapillaris can therefore provide important information about normal ageing and pathogenesis of visual impairment, and even some systemic diseases. In vivo imaging of the choriocapillaris has evolved from non-depth resolved, dye-based angiography to advanced, high resolution optical coherence tomography angiography (OCTA). However, the intricate microvascular networks within the choriocapillaris are still beyond the resolving limits of most OCTA instruments. Knowledge of histology, meticulous image acquisition methods, recognition of artifact and post-acquisition processing techniques are necessary for optimizing OCTA choriocapillaris images. Qualitative and quantitative analyses of the choriocapillaris provide clinical information in age-related macular degeneration (AMD), diabetic retinopathy (DR), pathologic myopia and central serous chorioretinopathy (CSC). Furthermore, studies have revealed choriocapillaris changes in posterior uveitis that are correlated with treatment outcome and have important prognostic significance. In addition to retinal diseases, choriocapillaris changes have been observed in systemic vascular diseases and complications associated with pregnancy.

    DOI: 10.1111/ceo.13984

    CASE REPORTS

    Epiretinal membrane-induced intraretinal neovascularization.

    Am J Ophthalmol Case Rep. 2021 Jul 24;23:101180.

    Giachos I, Chalkiadaki E, Andreanos K, Symeonidis C, Charonis A, Georgalas I, Rotsos T.

    PURPOSE: To report a 71-year-old male patient diagnosed with epiretinal membrane-induced intraretinal neovascularization.

    OBSERVATIONS: The presence of an epiretinal membrane (ERM) was confirmed by Optical Coherence Tomography (OCT), fluorescein and indocyanine angiography. Optical coherence tomography angiography (OCT-A) revealed a neovascular membrane within the ERM. Intravitreal ranibizumab injections were administered three times at four-week intervals. Imaging revealed a stable membrane with no leakage. Five months after the third injection, OCT revealed intraretinal fluid. OCT-A showed a new branch of the neo-vascular membrane at the superficial capillary plexus. Following an additional ranibizumab injection, the membrane stabilized.

    CONCLUSIONS AND IMPORTANCE: It is conceivable that neovascularization developed due to, or in close conjunction with an epiretinal membranes already in place.

    DOI: 10.1016/j.ajoc.2021.101180

    Coats’ Disease Diagnosed During Adulthood.

    Mandura RA, Alqahtani AS.

    Cureus. 2021 Jul 10;13(7):e16303.

    Coats’ disease is an idiopathic non-hereditary condition first described by Coats in 1908 as a congenital retinal telangiectatic and aneurysmal disease associated with retinal exudation. Its presentation is classically in early childhood. We report a rare case of Coats’ disease that first presented during adulthood in a 35-year-old male. The patient presented with visual loss in the left eye for two months. His visual acuity was counting fingers in the left eye and fundus examination revealed extensive lipid exudation in the macula with telangiectatic vessels and microaneurysms with vascular malformation in the inferotemporal quadrant. Fluorescein angiography showed leakage from the telangiectatic vessels, and optic coherence tomography showed significant macular edema. A provisional diagnosis of adult-onset Coats’ disease was made. The patient responded well to intravitreal ranibizumab injections for macular edema and sectoral argon laser photocoagulation for peripheral vascular abnormalities. This case is unusual in adulthood onset and the first presentation was during adulthood in the third decade of life in contrast to the typical age of onset which is younger than five years.

    DOI: 10.7759/cureus.16303

    REVIEWS

    Prevention of the Onset of Age-Related Macular Degeneration.

    J Clin Med. 2021 Jul 26;10(15):3297.

    Di Carlo E, Augustin AJ.

    Age-related macular degeneration (AMD) represents the leading cause of irreversible blindness in elderly people, mostly after the age of 65. The progressive deterioration of visual function in patients affected by AMD has a significant impact on quality of life and has also high social costs. The current therapeutic options are only partially able to slow down the natural course of the disease, without being capable of stopping its progression. Therefore, better understanding of the possibilities to prevent the onset of the disease is needed. In this regard, a central role is played by the identification of risk factors, which might participate to the development of the disease. Among these, the most researched are dietary risk factors, lifestyle, and light exposure. Many studies showed that a higher dietary intake of nutrients, such as lutein, zeaxanthin, beta carotene, omega-3 fatty acids and zinc, reduced the risk of early AMD. Regarding lifestyle habits, the association between smoking and AMD is currently accepted. Finally, retinal damage caused by ultraviolet rays and blue light is also worthy of attention. The scope of this review is to summarize the present knowledge focusing on the measures to adopt in order to prevent the onset of AMD.

    DOI: 10.3390/jcm10153297

    Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option.

    J Immunol Res. 2021 Jul 29;2021:9945725.

    Qin S, Dong N, Yang M, Wang J, Feng X, Wang Y.

    Age-related macular degeneration (AMD) is a multifactorial disease, which can culminate in irreversible vision loss and blindness in elderly. Nowadays, there is a big gap between dry AMD and wet AMD on treatment. Accounting for nearly 90% of AMD, dry AMD still lacks effective treatment. Numerous genetic and molecular researches have confirmed the significant role of the complement system in the pathogenesis of AMD, leading to a deeper exploration of complement inhibitors in the treatment of AMD. To date, at least 14 different complement inhibitors have been or are being explored in AMD in almost 40 clinical trials. While most complement inhibitors fail to treat AMD successfully, two of them are effective in inhibiting the rate of GA progression in phase II clinical trials, and both of them successfully entered phase III trials. Furthermore, recently emerging complement gene therapy and combination therapy also offer new opportunities to treat AMD in the future. In this review, we aim to introduce genetic and molecular associations between the complement system and AMD, provide the updated progress in complement inhibitors in AMD on clinical trials, and discuss the challenges and prospects of complement therapeutic strategies in AMD.

    DOI: 10.1155/2021/9945725