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    Research update: 521

    The latest research highlights for 29 November 2021.


    First-In-Human Robot-Assisted Subretinal Drug Delivery Under Local Anaesthesia A Randomised Clinical Trial 

    Am J Ophthalmol.2021 Nov 14;S0002-9394(21)00592-4. 

    Jasmina Cehajic-Kapetanovic, Kanmin Xue, Thomas L Edwards, Thijs C Meenink, Maarten J Beelen, Gerrit J Naus, Marc D de Smet, Robert E MacLaren

    Purpose: To report the results of a first-in-human study using a robotic device to assist subretinal drug delivery in patients undergoing vitreoretinal surgery for macular haemorrhage. 

    Design: Double armed, randomized controlled surgical trial ( identifier: NCT03052881). 

    Methods: Setting Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom. Participants In total, 12 participants were recruited: 6 in the robot-assisted and 6 in the control manual surgery arm according to the pre-specified inclusion and exclusion criteria. All subjects presented with acute loss of vision due to a sub-foveal haemorrhage secondary to neovascular age-related macular degeneration. Intervention After standard vitrectomy, intraoperative OCT-guided subretinal injection of tissue plasminogen activator (TPA) was performed either by robot-assisted or conventional manual technique under local anaesthesia. The robotic part of the procedure involved advancement of a cannula through the retina and stabilizing it during foot-controlled injection of up to 100µl of TPA solution. Main Outcome Measures We assessed surgical success, duration of surgery, adverse events, and tolerability of surgery under local anaesthesia. 

    Results: The procedure was well tolerated by all participants and safely performed in all cases. Total duration of surgery, time taken to complete the injection and retinal microtrauma were similar between the groups and not clinically significant. Subretinal haemorrhage was successfully displaced at 1-month post-intervention, except for one control subject, and the median gain in visual acuity was similar in both arms. 

    Conclusions: This first-in-human study demonstrates the feasibility and safety of high precision robot-assisted subretinal drug delivery as part of the surgical management of sub-macular haemorrhage, simulating its potential future application in gene or cell therapy. 

    DOI: 10.1016/j.ajo.2021.11.011 


    Visual Outcome and Treatment Frequency of Anti-VEGF Therapy Using the Treat-and-Extend and Treatment Cessation Regimen for Exudative Age-Related Macular Degeneration and Pachychoroid Neovasculopathy 

    Clin Ophthalmol.2021 Nov 9;15:4405-4418. 

    Takamasa Kinoshita, Junya Mori, Akira Hatanaka, Miho Shimizu, Hiroko Imaizumi 

    Purpose: To report the results of anti-vascular endothelial growth factor (VEGF) therapy using treat-and-extend (TAE) and treatment cessation regimens for exudative age-related macular degeneration (AMD) and pachychoroid neovasculopathy (PN). 

    Methods: We retrospectively studied 101 treatment-naïve eyes of 101 patients with exudative AMD and PN that underwent anti-VEGF therapy using TAE and treatment cessation regimen with a follow-up period of ≥12 months. Best-corrected visual acuity (BCVA), treatment frequency, and number of eyes with successful treatment cessation were measured. Successful treatment cessation was defined as dry macula retention without treatment for >16 weeks after the last injections. Factors related to the successful treatment cessation were evaluated. 

    Results: BCVA was maintained at the last visit with a mean follow-up period of 49.9 ± 26.9 months. The injection number decreased from 6.8 ± 2.31 at the first year to 3.7 ± 3.64 at the fifth year. At the last visit, 48 (47.5%) eyes were being treated at an interval of ≥12 weeks or were under treatment cessation. Successful treatment cessation during the follow-up period and at the last visit were achieved in 56 (55.4%) and 27 (26.7%) eyes, with a median treatment-free period of 66 and 126 weeks, respectively. Good early treatment response and a small recurrence number were associated with successful treatment cessation at the last visit. 

    Conclusion: Patients with good early response to treatment and fewer recurrences may achieve treatment cessation. This information could help physicians predict the achievement of treatment cessation for a considerable period. 

    DOI: 10.2147/OPTH.S334641 

    Contrast Sensitivity Changes in Center Involving Diabetic Macular Edema Treated with Aflibercept 

    Clin Ophthalmol.2021 Nov 11;15:4439-4445. 

    Donald R Nixon, Nicholas Flinn, Claudia Enderlein 

    Purpose: To characterize the changes in contrast sensitivity (CS) and retinal anatomy in patients with center involving diabetic macular edema (CDME) measured from baseline to post-loading doses of aflibercept. 

    Patients and methods: This single center, prospective, open-label, non-controlled evaluation of five aflibercept intravitreal injections for treatment of CDME over a 16-week period. One eye in each of the forty patients will receive aflibercept every 4 weeks. Subject testing includes measurements of central retinal thickness (CRT), best corrected visual acuity (BCVA), Pelli-Robson (PR) CS, and CamBlobs (CB) CS at 20 weeks post baseline. 

    Results: A total of 40 eyes from 40 patients with CDME were analyzed. The mean age was 62.9 ±10.6 years and 55% were male. At baseline, CRT was 365 ±94.6µm with logMAR BCVA 0.25±0.20. CS PR at baseline was 1.46±0.13 logCS compared to the normal population 1.79±0.10 logCS (P=<0.01), and the CS CB was 1.55±0.16 logCS compared to 1.92±0.08 logCS in the normal population (P=<0.01). At the completion of the study, CRT was decreased to 289 ±43.7µm (P=<0.001), and the logMAR BCVA improved to 0.18±0.02 (P=<0.05). At the same point the CS PR was 1.52±0.16 and CS CB was 1.62±0.16 logCS. At the end of the study 85% of eyes obtained BCVA of 0.3 logMAR or better. There was a reduction from baseline of 82.5% to 57.5% in the number of patients that had a CS that was two standard deviations below the mean. The greatest improvement in CS was associated with those patients that had the greatest reduction in CRT. 

    Conclusion: CS impairment in patients with CDME is significant. Although treatment can be associated with improvement, there still remains a group with decreased CS that could impact activities of daily living. Earlier intervention using reduction in CS as a metric may be associated with reduced residual deficit associated with treatment. 

    DOI: 10.2147/OPTH.S338478 

    Safety and efficacy of nurse led intravitreal injection service with Precivia® injection assist device 

    Eur J Ophthalmol.2021 Nov 18;11206721211060947. 

    Ibrar Ahmed, Panayiotis Maghsoudlou, Hani Hasan, Allaaeldin Abumattar, Nimish Shah

    Introduction: Intravitreal anti-VEGF injections are the most frequently performed outpatient procedure in the UK. Ophthalmic allied healthcare professionals are replacing medical professionals in delivering injections nationwide. The use of injection assist devices such as Precivia® has been well established and increasingly adopted to aid in their safe delivery. We present outcomes of nurse-led intravitreal injections using the Precivia® injection assist device over a five-year period in the UK. 

    Methods: A retrospective review was completed of all anti-VEGF intravitreal injections delivered at the Great Western Hospital between May 2015 and May 2020. 

    Results: Over the five-year study period, 2318 patients underwent a total of 26,923 intravitreal injections; 20,421 (75.8%) of which were delivered by appropriately trained ophthalmic nurses. The annual number of injections increased year-on-year from 2112 injections in 2015-2016 to 5410 injections in 2019-2020. The mean age of patients was 75.7±12.2 years with a female-to-male ratio was 1.17:1. Wet age-related macular degeneration represented the major indication for injections followed by retinal vein occlusion and diabetic maculopathy respectively. Three cases of post-injection endophthalmitis out of 20,421 (0.015%) injections in nurse injection group were identified during the study period. There were no cases of lens touch, retinal detachment or systemic thromboembolic events. 

    Conclusion: Use of the Precivia® intravitreal injection assist device by trained ophthalmic allied health professionals is a safe and cost-effective way to deliver intravitreal injections service. 

    DOI: 10.1177/11206721211060947 


    Persistent Hyper-Transmission Defects Detected on En Face Swept Source OCT Images Predict the Formation of Geographic Atrophy in AMD 

    Am J Ophthalmol.2021 Nov 13;S0002-9394(21)00577-8. 

    Rita Laiginhas, Yingying Shi, Mengxi Shen, Xiaoshuang Jiang, William Feuer, Giovanni Gregori, Philip J Rosenfeld

    Purpose: To determine if persistent hyper-transmission defects (hyperTDs), previously shown to have a greatest linear dimension (GLD) ≥ 250µm on en face swept source OCT (SS-OCT) images, serve as a stand-alone early biomarker for the future formation geographic atrophy (GA). 

    Design: Post-hoc cohort study using a subgroup of a prospective study. 

    Participants: Patients with intermediate age-related macular degeneration (iAMD). 

    Methods: All subjects underwent 6 × 6mm SS-OCT raster scans at baseline and during their follow-up period. En face images were generated using a slab with segmentation boundaries positioned 64µm to 400µm beneath Bruch’s membrane. Two graders independently evaluated all en face structural images for the presence of hyperTDs with a GLD ≥ 250µm and GA. 

    Results: A total of 190 eyes were included with a mean follow up of 31(SD: 13.2) months. At baseline, 31 eyes (16%) had at least one hyperTD ≥ 250µm and 13 eyes (42%) progressed to GA. In those eyes without a hyperTD ≥ 250µm at baseline, 42 (26%) developed hyperTDs ≥ 250µm during their follow-up and 11 eyes (7%) progressed to GA. At the last available follow-up visit, 25 eyes (13%) progressed to GA and of these 25 eyes, 24 eyes had a prior hyperTD ≥ 250µm detected before GA formed. A time-dependent Cox-survival regression analysis estimated an 80-fold (95% CI: 10.7 – 614, p<0.001) increased risk of developing GA once a hyperTD ≥ 250µm appeared. 

    Conclusions: Persistent hyperTDs detected on en face OCT images were shown to serve as an early stand-alone OCT biomarker for the future formation of GA. 

    DOI: 10.1016/j.ajo.2021.11.001 

    OCT Measurements of the Retinal Pigment Epithelium to Bruch’s Membrane Thickness around Geographic Atrophy Correlate with Growth: Short title: Thickened RPE/BM complex predicts faster GA growth 

    Am J Ophthalmol.2021 Nov 12;S0002-9394(21)00581-X. 

    Zhongdi Chu, Yingying Shi, Xiao Zhou, Liang Wang, Hao Zhou, Rita Laiginhas, Qinqin Zhang, Yuxuan Cheng, Mengxi Shen, Luis de Sisternes, Mary K Durbin, William Feuer, Giovanni Gregori, Philip J Rosenfeld, Ruikang K Wang

    Purpose: The retinal pigment epithelium (RPE) to Bruch’s membrane (BM) distance around geographic atrophy (GA) was measured using an optical attenuation coefficient (OAC) algorithm to determine if this measurement could serve as a clinical biomarker to predict the annual square root enlargement rate (ER) of GA. 

    Design: A retrospective analysis of a prospective, observational case series. 

    Methods: Eyes with GA secondary to age-related macular degeneration (AMD) were imaged with swept-source OCT (SS-OCT) using a 6 × 6 mm scan pattern. GA lesions were identified and measured using customized en face OCT images, and GA annual square root ERs were calculated. At baseline, the OACs were calculated from OCT datasets to generate customized en face OAC images for GA visualization. RPE-BM distances were measured using OAC data from different sub-regions around the GA. 

    Results: A total of 38 eyes from 27 subjects were included in this study. Measured RPE-BM distances were the highest in the region closest to GA. The RPE-BM distances immediately around the GA were significantly correlated with GA annual square root ERs (r = 0.595, p<0.001 for a 0-300 µm rim around the GA). No correlations were found between RPE-BM distances and previously published CC flow deficits in any sub-regions. 

    Conclusions: RPE-BM distances from regions around the GA significantly correlate with the annual ERs of GA. These results suggest that an abnormally thickened RPE/BM complex contributes to GA growth and this effect is independent of CC perfusion deficits. 

    DOI: 10.1016/j.ajo.2021.10.032

    Redefining response in wet AMD to anti VEGF therapy based on non-OCTA versus OCTA evaluation 

    Eur J Ophthalmol.2021 Nov 19;11206721211059349. 

    Anadi Khatri, Araniko Pandey, Kriti Joshi, Kinsuk Singh, Gunjan Prasai, Eli Pradhan, Rupesh Agrawal 

    Purpose: Anti vascular endothelial growth factor (anti VEGF) has been the mainstay of treatment in wet age-related macular degeneration (AMD). Subsequent decision to continue anti VEGF therapy depends on the treatment response quantified by functional (visual acuity) and morphological (optical coherence tomography) parameters then categorized from good to poor. 

    Methods: This study evaluates the agreement between OCT angiography (OCTA) and non-OCTA (logMAR VA plus OCT) to decide anti-VEGF treatment’s continuity. After an anti VEGF treatment, on a follow up visit, a patient underwent non-OCTA evaluation (decision A) then OCTA evaluation (decision B) to judge the necessity of future anti VEGF application. 

    Results: Out of 129 eyes, on 72 eyes (49%), there were agreements on both decision arms, but on 55 eyes (42%) there was disagreement. Particularly, disagreement on 47/55 eyes was important, where OCTA advised “continue anti VEGF” and non-OCTA advised “Stop anti VEGF” therapy. Cohen’s Kappa for probability of agreement to continue anti VEGF was fair (0.33) and to stop anti VEGF therapy was none (0.1). 

    Conclusions: Based on resulting disagreements between the two modalities on deciding the continuity of anti VEGF, we conclude that OCTA must be considered in the conventional decision making algorithm in patients with wet AMD under anti VEGF therapy. 

    DOI: 10.1177/11206721211059349 

    Aqueous humor cytokine levels through microarray analysis and a sub-analysis based on optical coherence tomography in wet age-related macular degeneration patients 

    BMC Ophthalmol.2021 Nov 18;21(1):399. 

    Jin-Ho Joo, Hyejee Kim, Jae-Ho Shin, Sang Woong Moon

    Background: To identify disease-specific cytokine and growth factor profile differences in the aqueous humor between wet age-related macular degeneration (AMD) patients and age-matched controls and to correlate their levels with the optical coherence tomography (OCT) findings. 

    Methods: Aqueous humors were obtained from 13 wet AMD eyes and 10 control eyes. Twenty cytokines and growth factors were measured using a RayBio antibody microarray technology in wet AMD and control eyes. 

    Results: The samples obtained from wet AMD patients exhibited a significantly increased expression of MCP-1, MIP-1α, MIP-1β, and vascular endothelial growth factor (VEGF). Subretinal fluid (SRF) patients showed significantly lower levels of proinflammatory cytokines, such as IL-1α and GM-CSF, than those without SRF. Pigment epithelial detachments (PED) patients showed lower levels of inflammatory cytokines, such as GM-CSF, IFN-γ, and TNF-α, than those without PED. Subretinal tissue (SRT) patients showed a higher level of IFN-γ than those without SRT. Compared with the controls, type 1 macular neovascularization (MNV) patients showed increased levels of MCP-1, MIP-1α, and MIP-1β, but not VEGF (p = 0.083). However, type 2 MNV patients showed increased levels of MCP-1 and VEGF (p = 0.040 and p = 0.040). 

    Conclusion: Inflammatory cytokines varied according to the type of AMD- and OCT-based parameters. Our observation of low levels of VEGF in patients with type 1 MNV implies that the inhibition of VEGF alone appears to be insufficient treatment for these patients and that cytokines such as MCP-1, MIP-1α, and MIP-1β should be modulated. And the presence of SRF in MNV may be associated with a positive prognosis because we found relatively low levels of proinflammatory cytokines. 

    DOI: 10.1186/s12886-021-02152-6 


    Understanding Drivers of Ocular Fibrosis: Current and Future Therapeutic Perspectives

    Int J Mol Sci.2021 Oct 29;22(21):11748. 

    Fabiana Mallone, Roberta Costi, Marco Marenco, Rocco Plateroti, Antonio Minni, Giuseppe Attanasio, Marco Artico, Alessandro Lambiase


    Ocular fibrosis leads to severe visual impairment and blindness worldwide, being a major area of unmet need in ophthalmology and medicine. To date, the only available treatments are antimetabolite drugs that have significant potentially blinding side effects, such as tissue damage and infection. There is thus an urgent need to identify novel targets to prevent/treat scarring and postsurgical fibrosis in the eye. In this review, the latest progress in biological mechanisms underlying ocular fibrosis are discussed. We also summarize the current knowledge on preclinical studies based on viral and non-viral gene therapy, as well as chemical inhibitors, for targeting TGFβ or downstream effectors in fibrotic disorders of the eye. Moreover, the role of angiogenetic and biomechanical factors in ocular fibrosis is discussed, focusing on related preclinical treatment approaches. Moreover, we describe available evidence on clinical studies investigating the use of therapies targeting TGFβ-dependent pathways, angiogenetic factors, and biomechanical factors, alone or in combination with other strategies, in ocular tissue fibrosis. Finally, the recent progress in cell-based therapies for treating fibrotic eye disorders is discussed. The increasing knowledge of these disorders in the eye and the promising results from testing of novel targeted therapies could offer viable perspectives for translation into clinical use. 

    DOI: 10.3390/ijms222111748