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    Research issue: 523

    The latest research highlights for 13 December 2021.


    Gut microbiota and age-related macular degeneration: A growing partnership 

    Surv Ophthalmol.2021 Nov 26;S0039-6257(21)00213-7. 

    Mário Lima-Fontes, Luís Meira, Pedro Barata, Manuel Falcão, Ângela Carneiro


    Age-related macular degeneration (AMD) is a leading cause of severe, irreversible vision impairment in developed countries, and its prevalence is rising all over the world, increasing sharply with age. AMD represents an acquired degeneration of the retina that causes significant central visual impairment through a combination of non-neovascular and neovascular derangement. The main risk factors for the development of advanced AMD are increasing age, genetic factors, and cigarette smoking; however, the exact pathophysiology of AMD is yet relatively poorly understood. In recent years, the gut microbiota has been intensively studied and linked to several pathologic processes, including ocular diseases. In this sense, the aim of this review is to gather published evidence about the relationship between gut microbiota and AMD.

    DOI: 10.1016/j.survophthal.2021.11.009 


    Correlation of Change in Central Subfield Thickness and Change in Visual Acuity in Neovascular AMD: Post Hoc Analysis of VIEW 1 and 2 

    Am J Ophthalmol.2021 Nov 27;S0002-9394(21)00617-6. 

    Onnisa Nanegrungsunk, Sophie Z Gu, Susan B Bressler, Weiming Du, Fouad Amer, Hadi Moini, Neil M Bressler

    Purpose: Determine correlation between change in central subfield thickness (CST) and change in best-corrected visual acuity (BCVA) in neovascular age-related macular degeneration (nAMD) receiving anti-VEGF agents. 

    Design: Post hoc analysis of VIEW 1 and 2 randomized clinical trials. 

    Methods: This analysis included participants randomized to ranibizumab 0.5 mg q4 weeks (Rq4), intravitreal aflibercept injection (IAI) 2 mg q4 weeks (2q4), and IAI q8 weeks after 3 monthly doses (2q8) to Week 52, followed by capped pro re nata (at least q12 weeks) dosing to Week 96. Relationship between changes in CST and BCVA was determined using Pearson correlation coefficient. 

    Results: Of 1815 eyes, 595 were assigned to Rq4, 613 to 2q4, and 607 to 2q8 arms. Correlations (95% confidence intervals [CI]) at Weeks 12, 52, and 96 were -0.08 (-0.17, 0.00), -0.05 (-0.14, 0.04), and -0.15 (-0.24, -0.06) for Rq4; -0.13 (-0.21, -0.04), -0.06 (-0.14, 0.03) and -0.04 (-0.13, 0.05) for 2q4, and -0.04 (-0.12, 0.05), -0.01 (-0.09, 0.08), and -0.01 (-0.10, 0.09) for 2q8. Linear regression analysis adjusted for relevant baseline factors showed CST changes accounted for 11% of BCVA changes. Every 100 µm decrease in CST was associated with 0.3 letter decrease (P = .25) at Week 52 and 0.14 letter decrease (P = .69) at Week 96. 

    Conclusions: Weak or no correlation was found between changes in CST and BCVA with either agent or regimen, suggesting changes in CST should not be used as a surrogate for visual acuity outcomes in nAMD. 

    DOI: 10.1016/j.ajo.2021.11.020 


    Selective retina therapy and thermal stimulation of the retina: different regenerative properties – implications for AMD therapy 

    BMC Ophthalmol.2021 Nov 30;21(1):412. 

    Elisabeth Richert, Julia Papenkort, Claus von der Burchard, Alexa Klettner, Philipp Arnold, Ralph Lucius, Ralf Brinkmann, Carsten Framme, Johann Roider, Jan Tode

    Background: Selective Retina Therapy (SRT), a photodisruptive micropulsed laser modality that selectively destroys RPE cells followed by regeneration, and Thermal Stimulation of the Retina (TSR), a stimulative photothermal continuous wave laser modality that leads to an instant sublethal temperature increase in RPE cells, have shown therapeutic effects on Age-related Macular Degeneration (AMD) in mice. We investigate the differences between both laser modalities concerning RPE regeneration. 

    Methods: For PCR array, 6 eyes of murine AMD models, apolipoprotein E and nuclear factor erythroid-derived 2- like 2 knock out mice respectively, were treated by neuroretina-sparing TSR or SRT. Untreated litter mates were controls. Eyes were enucleated either 1 or 7 days after laser treatment. For morphological analysis, porcine RPE/choroid organ cultures underwent the same laser treatment and were examined by calcein vitality staining 1 h and 1, 3 or 5 days after irradiation. 

    Results: TSR did not induce the expression of cell-mediators connected to cell death. SRT induced necrosis associated cytokines as well as inflammation 1 but not 7 days after treatment. Morphologically, 1 h after TSR, there was no cell damage. One and 3 days after TSR, dense chromatin and cell destruction of single cells was seen. Five days after TSR, there were signs of migration and proliferation. In contrast, 1 h after SRT a defined necrotic area within the laser spot was seen. This lesion was closed over days by migration and proliferation of adjacent cells. 

    Conclusions: SRT induces RPE cell death, followed by regeneration within a few days. It is accompanied by necrosis induced inflammation, RPE proliferation and migration. TSR does not induce immediate RPE cell death; however, migration and mitosis can be seen a few days after laser irradiation, not accompanied by necrosis-associated inflammation. Both might be a therapeutic option for the treatment of AMD. 

    DOI: 10.1186/s12886-021-02188-8 


    Spectral fundus autofluorescence peak emission wavelength in ageing and AMD 

    Acta Ophthalmol.2021 Dec 1. 

    Rowena Schultz, Linda Schwanengel, Daniel Meller, Martin Hammer

    Purpose: To investigate the spectral characteristics of fundus autofluorescence (FAF) in AMD patients and controls. 

    Methods: Fundus autofluorescence spectral characteristics was described by the peak emission wavelength (PEW) of the spectra. Peak emission wavelength (PEW) was derived from the ratio of FAF recordings in two spectral channels at 500-560 nm and 560-720 nm by fluorescence lifetime imaging ophthalmoscopy. The ratio of FAF intensity in both channels was related to PEW by a calibration procedure. Peak emission wavelength (PEW) measurements were done in 44 young (mean age: 24.0 ± 3.8 years) and 18 elderly (mean age: 67.5 ± 10.2 years) healthy subjects as well as 63 patients with AMD (mean age: 74.0 ± 7.3 years) in each pixel of a 30° imaging field. The values were averaged over the central area, the inner and the outer ring of the ETDRS grid. 

    Results: There was no significant difference between PEW in young and elderly controls. However, PEW was significantly shorter in AMD patients (ETDRS grid centre: 571 ± 26 nm versus 599 ± 17 nm for elderly controls, inner ring: 596 ± 17 nm versus 611 ± 11 nm, outer ring: 602 ± 16 nm versus 614 ± 11 nm). After a mean follow-up time of 50.8 ± 10.8 months, the PEW in the patients decreased significantly by 9 ± 19 nm in the inner ring of the grid. Patients, showing progression to atrophic AMD in the follow up, had significantly (p ≤ 0.018) shorter PEW at baseline than non-progressing patients. 

    Conclusions: Peak emission wavelength (PEW) is related to AMD pathology and might be a diagnostic marker in AMD. Possibly, a short PEW can predict progression to retinal and/or pigment epithelium atrophy. 

    DOI: 10.1111/aos.15070 

    Acquired Vitelliform Macular Degeneration: Characteristics and Challenges of Managing Subretinal Fluid 

    J Ophthalmic Vis Res.2021 Oct 25;16(4):582-591. 

    Joseph Juliano, Sagar Patel, Hossein Ameri

    Purpose: To highlight diagnostic challenges in patients with acquired vitelliform macular degeneration (AVMD) with subretinal fluid (SRF) and to examine the characteristics of image findings in patients with AVMD. 

    Methods: In this retrospective review, the electronic medical record of 22 eyes of 16 patients with AVMD was studied. The rates of SRF, drusen, pigment epithelial detachment (PED), and patient clinical information such as age, length of follow-up, and best-corrected visual acuity (BCVA) were assessed. 

    Results: The mean age at diagnosis with AVMD was 72 years with a mean follow-up time of 29 months. Median BCVA 20/33 at presentation and 20/33 at final follow-up. Drusen was found in 13 of 22 eyes (59.1%), PEDs in 4 of 22 eyes (18.2%), and SRF in 10 of 22 eyes (45.5%) at some point during their follow-up. Of the 10 eyes with SRF, 70% were center involving, and recurrence occurred in 40%, all in the same location as the initial presentation of SRF. Three eyes received an anti-vascular endothelial growth factor injection for SRF. In 66% of cases receiving an injection, the fluid later relapsed and remitted without further injections during the course of follow-up. 

    Conclusion: AVMD occurs in the same demographic as age-related macular degeneration (AMD) and has many common features. SRF in AVMD tends to be center involving and recurs usually in the same location as its origin. The use of anti-VEGF injections did not seem to improve SRF in contrast to the SRF seen in wet AMD. Proper differentiation of AVMD may prevent unnecessary long-term treatment with intravitreal anti-VEGF injections. 

    DOI: 10.18502/jovr.v16i4.9748 

    Morphologic and Microvascular Differences Between Macular Neovascularization with and without Subretinal Fibrosis

    Transl Vis Sci Technol.2021 Dec 1;10(14):1. 

    Philipp Ken Roberts, Markus Schranz, Alice Motschi, Sylvia Desissaire, Valentin Hacker, Michael Pircher, Stefan Sacu, Wolf Buehl, Christoph Konrad Hitzenberger, Ursula Schmidt-Erfurth

    Purpose: To evaluate morphologic and microvascular differences between eyes with and without subretinal fibrosis (SF) caused by neovascular age-related macular degeneration (nAMD). 

    Methods: Patients with nAMD with a minimum history of 12 months of anti-VEGF treatment were prospectively included in this cross-sectional study. Patients were imaged using standard imaging, swept-source optical coherence tomography angiography for quantitative microvascular analysis and polarization-sensitive OCT as an ancillary method for automated SF segmentation. The presence of reticular pseudodrusen, hyperreflective foci (HRF), and outer retinal tubulation (ORT) were also evaluated. 

    Results: Sixty eyes of 60 participants (37 female) with nAMD and a mean 3.1 (±2.7)-year history of anti-VEGF treatment were included, 20 (33%) of which were diagnosed with SF. Eyes with SF had a higher prevalence of ORT (P < 0.001) and a lower prevalence of HRF (P = 0.004) than eyes without SF. Fifty eyes were analyzed quantitatively for microvascular biomarkers. Eyes with SF had a larger greatest vascular caliber (P = 0.001) and greatest linear diameter (P = 0.042), a larger microvascular neovascularization (MNV) area (P = 0.026), larger vessel area (P = 0.037), higher number of vessel junctions (P = 0.025), longer total vessel length (P = 0.027), higher number of vessel endpoints (P = 0.007), and higher endpoint density (P = 0.047). 

    Conclusions: This multimodal imaging approach demonstrated in vivo microvascular and morphological differences in eyes with and without SF. Eyes with SF tend to have larger MNV lesions with thicker vessels and are often associated with the presence of ORT. 

    Translational relevance: This study points out imaging biomarkers in patients with SF, which may help identifying high-risk patients. 

    DOI: 10.1167/tvst.10.14.1 


    Should clinical automated perimetry be considered for routine functional assessment of early/intermediate age-related macular degeneration (AMD)? A systematic review of current literature 

    Ophthalmic Physiol Opt.2022 Jan;42(1):161-177. 

    Matt Trinh, Michael Kalloniatis, Lisa Nivison-Smith

    Purpose: There is growing interest in functional testing for early/intermediate age-related macular degeneration (iAMD). However, systematic evaluation of existing clinical functional tests is lacking. This systematic review examines evidence for using clinical automated perimetry in routine assessment of early/iAMD. 

    Recent findings: PubMed, Web of Science Core Collection, and Embase were searched from inception to October 2020 to answer, is there evidence of visual field defects in early/iAMD, and if so, are early/iAMD visual field defects linked to real-world patient outcomes? Articles using clinical automated perimetry (commercially accessible and non-modified devices/protocols) were included. Microperimetry was excluded as this has yet to be incorporated into clinical guidelines. The primary outcome was global visual field indices including mean deviation (MD), pattern standard deviation (PSD), mean sensitivity (MS) and frequency of defects. The secondary outcome was any real-world patient outcome including quality of life and/or activities of daily living indices. Twenty-six studies were eligible for inclusion and all studies were observational. There was consistent evidence of worsened MD, PSD, MS and frequency of defects for early/iAMD compared to normal eyes under photopic, low-photopic and scotopic conditions. Meta-analysis of studies using standard automated perimetry (SAP) under photopic conditions revealed worsened MD (-1.52dB [-2.27, -0.78 dB]) and MS (-1.47dB [-2, -0.94 dB]) in early/iAMD compared to normal eyes, representing large statistical effect sizes but non-clinically meaningful reductions. There was insufficient data for meta-analyses regarding other clinical automated perimetry protocols. Only one study assessed a real-world patient outcome (on-road driving performance), with no significant link to visual field outcomes in early/iAMD. 

    Summary: Significant reduction of global visual field indices is present in early/iAMD, but not clinically meaningful using SAP under photopic conditions. Translational relevance of visual field outcomes to patient outcomes in early/iAMD remains unclear. Thus, SAP under photopic conditions is unlikely to be useful for routine assessment of early/iAMD. 

    DOI: 10.1111/opo.12919 

    Quantitative Imaging Biomarkers in Age-Related Macular Degeneration and Diabetic Eye Disease: A Step Closer to Precision Medicine 

    J Pers Med.2021 Nov 8;11(11):1161. 

    Gagan Kalra, Sudeshna Sil Kar, Duriye Damla Sevgi, Anant Madabhushi, Sunil K Srivastava, Justis P Ehlers


    The management of retinal diseases relies heavily on digital imaging data, including optical coherence tomography (OCT) and fluorescein angiography (FA). Targeted feature extraction and the objective quantification of features provide important opportunities in biomarker discovery, disease burden assessment, and predicting treatment response. Additional important advantages include increased objectivity in interpretation, longitudinal tracking, and ability to incorporate computational models to create automated diagnostic and clinical decision support systems. Advances in computational technology, including deep learning and radiomics, open new doors for developing an imaging phenotype that may provide in-depth personalized disease characterization and enhance opportunities in precision medicine. In this review, we summarize current quantitative and radiomic imaging biomarkers described in the literature for age-related macular degeneration and diabetic eye disease using imaging modalities such as OCT, FA, and OCT angiography (OCTA). Various approaches used to identify and extract these biomarkers that utilize artificial intelligence and deep learning are also summarized in this review. These quantifiable biomarkers and automated approaches have unleashed new frontiers of personalized medicine where treatments are tailored, based on patient-specific longitudinally trackable biomarkers, and response monitoring can be achieved with a high degree of accuracy. 

    DOI: 10.3390/jpm11111161