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    Research update: 502

    The latest research highlights for 28 June 2021.

    28 June 2021


    Impact of neovascular age-related macular degeneration: burden of patients receiving therapies in Japan

    Sci Rep. 2021 Jun 23;11(1):13152.

    Shigeru Honda, Yasuo Yanagi, Hideki Koizumi, Yirong Chen, Satoru Tanaka, Manami Arimoto, Kota Imai 

    PMID: 34162934 PMCID: PMC8222235 DOI: 10.1038/s41598-021-92567-4

    The chronic eye disorder, neovascular age-related macular degeneration (nAMD), is a common cause of permanent vision impairment and blindness among the elderly in developed countries, including Japan. This study aimed to investigate the disease burden of nAMD patients under treatment, using data from the Japan National Health and Wellness surveys 2009-2014. Out of 147,272 respondents, 100 nAMD patients reported currently receiving treatment. Controls without nAMD were selected by 1:4 propensity score matching. Healthcare Resource Utilisation (HRU), Health-Related Quality of Life (HRQoL), and work productivity loss were compared between the groups. Regarding HRU, nAMD patients had significantly increased number of visits to any healthcare provider (HCP) (13.8 vs. 8.2), ophthalmologist (5.6 vs. 0.8), and other HCP (9.5 vs. 7.1) compared to controls after adjusting for confounding factors. Additionally, nAMD patients had reduced HRQoL and work productivity, i.e., reduced physical component summary (PCS) score (46.3 vs. 47.9), increased absenteeism (18.14% vs. 0.24%), presenteeism (23.89% vs. 12.44%), and total work productivity impairment (33.57% vs. 16.24%). The increased number of ophthalmologist visits were associated with decreased PCS score, increased presenteeism and total work productivity impairment. The current study highlighted substantial burden for nAMD patients, requiring further attention for future healthcare planning and treatment development.


    The impact of compliance among patients with diabetic macular oedema treated with intravitreal aflibercept: a 48-month follow-up study

    Acta Ophthalmol. 2021 Jun 17.

    Reinhard Angermann, Markus Hofer, Anna Lena Huber, Teresa Rauchegger, Yvonne Nowosielski, Marina Casazza, Valeria Falanga, Claus Zehetner  

    PMID: 34145756 DOI: 10.1111/aos.14946

    Purpose: This study aimed to compare anatomical and functional outcomes between patients with non-proliferative diabetic retinopathy (NPDR) with diabetic macular oedema (DME) who adhered to intravitreal aflibercept therapy and patients lost to follow-up (LTFU).

    Methods: We enrolled 200 patients and recorded the interval between each procedure and the subsequent follow-up visit. Moreover, visual acuity (VA) and anatomical outcomes were measured at each follow-up examination.

    Results: Among the patients, 103 (51%) patients adhered to intravitreal aflibercept therapy and follow-up examination while 97 (49%) patients were LTFU. Forty-six (47%) patients LTFU who returned for further treatment showed a significant decrease in VA from 0.51 (±0.46) to 0.89 (±0.38) logarithm of the minimum angle of resolution (logMAR) after 48 months (p = 0.004). Compared with the adherent group, the return group showed a worse VA at 48 months (p = 0.036). Further, 1 (1%) patient in the adherent group and 8 (17%) patients in the return group developed a proliferative DR. Patients who were LTFU had a 13.0 times greater chance to develop a proliferative DR (p = 0.022).

    Conclusions: Patients who did not adhere to intravitreal aflibercept therapy for DME showed significantly worse visual outcomes compared to patients with good therapy adherence. Moreover, patients with LTFU had a 13 times higher risk of developing a proliferative DR. Considering the potential disease progress, better strategies should be applied to optimize the functional outcome of patients at risk of reduced adherence.


    Growth Modeling for Quantitative, Spatially Resolved Geographic Atrophy Lesion Kinetics

    Transl Vis Sci Technol. 2021 Jun 1;10(7):26.

    Eric M Moult, Yunchan Hwang, Yingying Shi, Liang Wang, Siyu Chen, Nadia K Waheed, Giovanni Gregori, Philip J Rosenfeld, James G Fujimoto  

    PMID: 34156431 DOI: 10.1167/tvst.10.7.26

    Purpose: To demonstrate the applicability of a growth modeling framework for quantifying spatial variations in geographic atrophy (GA) lesion kinetics.

    Methods: Thirty-eight eyes from 27 patients with GA secondary to age-related macular degeneration were imaged with a commercial swept source optical coherence tomography instrument at two visits separated by 1 year. Local GA growth rates were computed at 6-µm intervals along each lesion margin using a previously described growth model. Corresponding margin eccentricities, margin angles, and growth angles were also computed. The average GA growth rates conditioned on margin eccentricity, margin angle, growth angle, and fundus position were estimated via kernel regression.

    Results: A total of 88,356 GA margin points were analyzed. The average GA growth rates exhibited a hill-shaped dependency on eccentricity, being highest in the 0.5 mm to 1.6 mm range and lower on either side of that range. Average growth rates were also found to be higher for growth trajectories oriented away from (smaller growth angle), rather than toward (larger growth angle), the foveal center. The dependency of average growth rate on margin angle was less pronounced, although lesion segments in the superior and nasal aspects tended to grow faster.

    Conclusions: Our proposed growth modeling framework seems to be well-suited for generating accurate, spatially resolved GA growth rate atlases and should be confirmed on larger datasets.

    Translational relevance: Our proposed growth modeling framework may enable more accurate measurements of spatial variations in GA growth rates.


    CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function

    Nat Commun. 2021 Jun 23;12(1):3906.

    Saumil Sethna, Patrick A Scott, Arnaud P J Giese, Todd Duncan, Xiaoying Jian, Sheikh Riazuddin, Paul A Randazzo, T Michael Redmond, Steven L Bernstein, Saima Riazuddin, Zubair M Ahmed  

    PMID: 34162842 DOI: 10.1038/s41467-021-24056-1

    Age-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling-a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.

    Active Rap1-mediated inhibition of choroidal neovascularization requires interactions with IQGAP1 in choroidal endothelial cells

    FASEB J. 2021 Jul;35(7):e21642.

    Aniket Ramshekar, Haibo Wang, Eric Kunz, Christian Pappas, Gregory S Hageman, Brahim Chaqour, David B Sacks, M Elizabeth Hartnett 

    PMID: 34166557 DOI: 10.1096/fj.202100112R

    Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The pathophysiology involves activation of choroidal endothelial cells (CECs) to transmigrate the retinal pigment epithelial (RPE) monolayer and form choroidal neovascularization (CNV) in the neural retina. The multidomain GTPase binding protein, IQGAP1, binds active Rac1 and sustains activation of CECs, thereby enabling migration associated with vision-threatening CNV. IQGAP1 also binds the GTPase, Rap1, which when activated reduces Rac1 activation in CECs and CNV. In this study, we tested the hypothesis that active Rap1 binding to IQGAP1 is necessary and sufficient to reduce Rac1 activation in CECs, and CNV. We found that pharmacologic activation of Rap1 or adenoviral transduction of constitutively active Rap1a reduced VEGF-mediated Rac1 activation, migration, and tube formation in CECs. Following pharmacologic activation of Rap1, VEGF-mediated Rac1 activation was reduced in CECs transfected with an IQGAP1 construct that increased active Rap1-IQGAP1 binding but not in CECs transfected with an IQGAP1 construct lacking the Rap1 binding domain. Specific knockout of IQGAP1 in endothelial cells reduced laser-induced CNV and Rac1 activation in CNV lesions, but pharmacologic activation of Rap1 did not further reduce CNV compared to littermate controls. Taken together, our findings provide evidence that active Rap1 binding to the IQ domain of IQGAP1 is sufficient to interfere with active Rac1-mediated CEC activation and CNV formation.

    Role of Junctional Adhesion Molecule-C in the Regulation of Inner Endothelial Blood-Retinal Barrier Function

    Front Cell Dev Biol. 2021 Jun 7;9:695657.

    Xu Hou, Hong-Jun Du, Jian Zhou, Dan Hu, Yu-Sheng Wang, Xuri Li  

    PMID: 34164405 PMCID: PMC8215391 DOI: 10.3389/fcell.2021.695657

    Although JAM-C is abundantly expressed in the retinae and upregulated in choroidal neovascularization (CNV), it remains thus far poorly understood whether it plays a role in the blood-retinal barrier, which is critical to maintain the normal functions of the eye. Here, we report that JAM-C is highly expressed in retinal capillary endothelial cells (RCECs), and VEGF or PDGF-C treatment induced JAM-C translocation from the cytoplasm to the cytomembrane. Moreover, JAM-C knockdown in RCECs inhibited the adhesion and transmigration of macrophages from wet age-related macular degeneration (wAMD) patients to and through RCECs, whereas JAM-C overexpression in RCECs increased the adhesion and transmigration of macrophages from both wAMD patients and healthy controls. Importantly, the JAM-C overexpression-induced transmigration of macrophages from wAMD patients was abolished by the administration of the protein kinase C (PKC) inhibitor GF109203X. Of note, we found that the serum levels of soluble JAM-C were more than twofold higher in wAMD patients than in healthy controls. Mechanistically, we show that JAM-C overexpression or knockdown in RCECs decreased or increased cytosolic Ca2+ concentrations, respectively. Our findings suggest that the dynamic translocation of JAM-C induced by vasoactive molecules might be one of the mechanisms underlying inner endothelial BRB malfunction, and inhibition of JAM-C or PKC in RCECs may help maintain the normal function of the inner BRB. In addition, increased serum soluble JAM-C levels might serve as a molecular marker for wAMD, and modulating JAM-C activity may have potential therapeutic value for the treatment of BRB malfunction-related ocular diseases.

    Differential and Altered Spatial Distribution of Complement Expression in Age-Related Macular Degeneration

    Invest Ophthalmol Vis Sci. 2021 Jun 1;62(7):26.

    John T Demirs, Junzheng Yang, Maura A Crowley, Michael Twarog, Omar Delgado, Yubin Qiu, Stephen Poor, Dennis S Rice, Thaddeus P Dryja, Karen Anderson, Sha-Mei Liao 

    PMID: 34160562 DOI: 10.1167/iovs.62.7.26

    Purpose: Dysregulation of the alternative complement pathway is a major pathogenic mechanism in age-related macular degeneration. We investigated whether locally synthesized complement components contribute to AMD by profiling complement expression in postmortem eyes with and without AMD.

    Methods: AMD severity grade 1 to 4 was determined by analysis of postmortem acquired fundus images and hematoxylin and eosin stained histological sections. TaqMan (donor eyes n = 39) and RNAscope/in situ hybridization (n = 10) were performed to detect complement mRNA. Meso scale discovery assay and Western blot (n = 31) were used to measure complement protein levels.

    Results: The levels of complement mRNA and protein expression were approximately 15- to 100-fold (P < 0.0001-0.001) higher in macular retinal pigment epithelium (RPE)/choroid tissue than in neural retina, regardless of AMD grade status. Complement mRNA and protein levels were modestly elevated in vitreous and the macular neural retina in eyes with geographic atrophy (GA), but not in eyes with early or intermediate AMD, compared to normal eyes. Alternative and classical pathway complement mRNAs (C3, CFB, CFH, CFI, C1QA) identified by RNAscope were conspicuous in areas of atrophy; in those areas C3 mRNA was observed in a subset of IBA1+ microglia or macrophages.

    Conclusions: We verified that RPE/choroid contains most ocular complement; thus RPE/choroid rather than the neural retina or vitreous is likely to be the key site for complement inhibition to treat GA or earlier stage of the disease. Outer retinal local production of complement mRNAs along with evidence of increased complement activation is a feature of GA.

    Tick-over mediated complement activation is sufficient to cause basal deposit formation in cell-based models of macular degeneration

    J Pathol. 2021 Jun 21.

    Blanca Chinchilla, Parthena Foltopoulou, Rosario Fernandez-Godino  

    PMID: 34155630 DOI: 10.1002/path.5747

    Despite numerous unsuccessful clinical trials for anti-complement drugs to treat age-related macular degeneration (AMD), the complement system has not been fully explored as a target to stop drusen growth in patients with dry AMD. We propose that the resilient autoactivation of C3 by hydrolysis of its internal thioester (tick-over), which cannot be prevented by existing drugs, plays a critical role in the formation of drusenoid deposits underneath the retinal pigment epithelium (RPE). We have combined gene editing tools with stem cell technology to generate cell-based models that allow the role of the tick-over in sub-RPE deposit formation to be studied. The results demonstrate that structurally or genetically driven pathological events affecting the RPE and Bruch’s membrane can lead to dysregulation of the tick-over, which is sufficient to stimulate the formation of sub-RPE deposits. This can be prevented with therapies that downregulate C3 expression.

    A nonhuman primate model of blue light-induced progressive outer retina degeneration showing brimonidine drug delivery system-mediated cyto- and neuroprotection

    Exp Eye Res. 2021 Jun 18;108678.

    Lakshmi Rajagopalan, Corine Ghosn, Mitalee Tamhane, Alexandra Almazan, Lydia Andrews-Jones, Ashutosh Kulkarni, Lori-Ann Christie, James Burke, Francisco J López, Michael Engles  

    PMID: 34153289 DOI: 10.1016/j.exer.2021.108678

    Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) characterized by atrophy of the retinal pigment epithelium (RPE), loss of photoreceptors, and disruption of choriocapillaris. Excessive light exposure is toxic to the retina and is a known risk factor for AMD. We first investigated the effects of blue light-induced phototoxicity on RPE and photoreceptors in nonhuman primates (NHPs, a model of progressive retinal degeneration) and then evaluated the potential cyto- and neuroprotective effects of the brimonidine drug delivery system (Brimo DDS). In the first set of experiments related to model development, parafoveal lesions of varying severity were induced using blue light irradiation of the retina of cynomolgus monkeys to evaluate the level of phototoxicity in the RPE and photoreceptors. RPE damage was assessed using fundus autofluorescence imaging to quantify areas of hypofluorescence, while thinning of the outer nuclear layer (ONL, photoreceptor nuclei) was quantified using optical coherence tomography (OCT). Photoreceptor function was assessed using multifocal electroretinography (mfERG). RPE damage progressively increased across all lesion severities from 2 to 12 weeks, as did the extent of ONL thinning. Lesions of high severity continued to show reduction in mfERG amplitude, reaching a statistically significant maximum reduction at 12 weeks. Collectively, the first set of experiments showed that blue light irradiation of the NHP eye resulted in progressive retinal degeneration identified by damage to RPE, ONL thinning, and disrupted photoreceptor function – hallmarks of GA in humans. We then used the model to evaluate the cyto- and neuroprotective effects of Brimo DDS, administered as a therapeutic after allowing the lesions to develop for 5 weeks. Placebo DDS or Brimo DDS were administered intravitreally and a set of untreated animals were used as an additional control. In the placebo DDS group, hypofluorescence area continued to increase from baseline, indicating progressive RPE damage, while progression was significantly slowed in eyes receiving Brimo DDS. Likewise, ONL thinning continued to progress over time in eyes that received the placebo DDS, but was reduced in Brimo DDS-treated eyes. Pharmacologically relevant brimonidine concentrations were sustained in the retina for up to 26 weeks following Brimo DDS administration. In summary, Brimo DDS demonstrated cyto- and neuroprotective effects in a novel NHP GA model of progressive retinal degeneration.

    Cytokine and Chemokine Profile Changes in Patients with Neovascular Age-Related Macular Degeneration After Intravitreal Ranibizumab Injection for Choroidal Neovascularization

    Drug Des Devel Ther. 2021 Jun 9;15:2457-2467.

    Tingting Sun, Qingquan Wei, Peng Gao, Yongjie Zhang, Qing Peng  

    PMID: 34140764 PMCID: PMC8203097 DOI: 10.2147/DDDT.S307657

    Objective: To investigate the concentrations of cytokine and chemokines profiling in aqueous humor for choroidal neovascularization (CNV) due to neovascular age-related macular degeneration (nAMD) before and during Intravitreal injection of ranibizumab (IVR) and its relation with the disease’s active state.

    Methods: The cytokine levels in aqueous humour were detected by the Bio-Plex® 200 System and the Bio-Plex™ Human Cytokine Standard 27-Plex, Group I. Aqueous humour samples of experimental group were collected from 19 patients diagnosed nAMD at baseline and at 1 month after IVR. Aqueous humour samples of control group were collected from 20 patients undergoing cataract surgery.

    Results: Aqueous humor levels of basic fibroblast growth factor (basic FGF) and RANTES were significantly lower in nAMD patients than in the control group (P=0.044 and P<0.001, respectively). Vascular endothelial growth factor-A (VEGF-A) was significantly higher in nAMD patients than in the control group (P < 0.001). The average Eotaxin levels were significantly higher in nAMD patients after IVR than before (P=0.03). Contrarily, the average VEGF-A levels were significantly lower in AMD patients after IVR than before (P < 0.001).

    Conclusion: Angiogenic, growth factors and inflammatory are involved in the formation of neovascularization of AMD patients. IVR did not cause significant differences in any growth factors or inflammatory cytokines in nAMD patients with the exception of VEGF.


    Vision, Eye Disease, and the Onset of Balance Problems: The Canadian Longitudinal Study on Aging: Vision and Balance Problems

    Am J Ophthalmol. 2021 Jun 19;S0002-9394(21)00330-5.

    Zaina Kahiel, Alyssa Grant, Marie-Josée Aubin, Ralf Buhrmann, Marie-Jeanne Kergoat, Ellen E Freeman 

    PMID: 34157278 DOI: 10.1016/j.ajo.2021.06.008

    Purpose: To understand the relationship between visual impairment, self-reported eye disease, and the onset of balance problems.

    Design: Population-based prospective cohort study METHODS: : Baseline and 3-year follow-up data were used from the Canadian Longitudinal Study on Aging. The Comprehensive Cohort included 30,097 adults ages 45-85 years old recruited from 11 sites across 7 provinces. Balance was measured using the one-leg balance test. Those who could not stand on one leg for at least 60 seconds failed the balance test. Presenting visual acuity was measured using the Early Treatment of Diabetic Retinopathy Study chart. Participants were asked about a previous diagnosis of cataract, macular degeneration, or glaucoma. Logistic regression was used.

    Results: Of the 12,158 people who could stand for 60 seconds on one leg at baseline, 18% were unable to do the same 3 years later. For each line worse of visual acuity, there was a 15% higher odds of failing the balance test at follow-up (odds ratio (OR)=1.15, 95% confidence interval (CI) 1.10, 1.20) after adjustment. Those with a report of a former (OR=1.59, 95% CI 1.17, 2.16) or current cataract (OR=1.31, 95% CI 1.01, 1.68) were more likely to fail the test at follow-up. AMD and glaucoma were not associated with failure on the balance test.

    Conclusion: These data provide longitudinal evidence that vision loss increases the odds of balance problems over a 3-year period. Efforts to prevent avoidable vision loss are needed as are efforts to improve the balance of visually impaired people.


    Epistatic interactions of genetic loci associated with age-related macular degeneration

    Sci Rep. 2021 Jun 23;11(1):13114.

    Christina Kiel, Christoph A Nebauer, Tobias Strunz, Simon Stelzl, Bernhard H F Weber

    PMID: 34162900 PMCID: PMC8222216 DOI: 10.1038/s41598-021-92351-4

    The currently largest genome-wide association study (GWAS) for age-related macular degeneration (AMD) defines disease association with genome-wide significance for 52 independent common and rare genetic variants across 34 chromosomal loci. Overall, these loci contain over 7200 variants and are enriched for genes with functions indicating several shared cellular processes. Still, the precise mechanisms leading to AMD pathology are largely unknown. Here, we exploit the phenomenon of epistatic interaction to identify seemingly independent AMD-associated variants that reveal joint effects on gene expression. We focus on genetic variants associated with lipid metabolism, organization of extracellular structures, and innate immunity, specifically the complement cascade. Multiple combinations of independent variants were used to generate genetic risk scores allowing gene expression in liver to be compared between low and high-risk AMD. We identified genetic variant combinations correlating significantly with expression of 26 genes, of which 19 have not been associated with AMD before. This study defines novel targets and allows prioritizing further functional work into AMD pathobiology.

    Prevalence and Phenotype Associations of Complement Factor I Mutations in Geographic Atrophy

    Hum Mutat. 2021 Jun 21.

    Adnan H Khan, Janice Sutton, Angela J Cree, Samir Khandhadia, Gabriella De Salvo, John Tobin, Priya Prakash, Rashi Arora, Winfried Amoaku, Peter Charbel Issa, Robert E MacLaren, Paul N Bishop, Tunde Peto, Quresh Mohamed, David H Steel, Sobha Sivaprasad, Clare Bailey, Geeta Menon, David Kavanagh, Andrew J Lotery  

    PMID: 34153144 DOI: 10.1002/humu.24242

    Rare variants in the Complement Factor I (CFI) gene, associated with low serum Factor I (FI) levels, are strong risk factors for developing the advanced stages of Age-Related Macular Degeneration (AMD). No studies have been undertaken on the prevalence of disease-causing CFI mutations in patients with Geographic Atrophy (GA) secondary to AMD. A multi-centre, cross-sectional, non-interventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype-phenotype study was performed. Four hundred and sixty-eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n=91) demonstrated a low serum FI concentration (below 15.6 μg/ml). CFI gene sequencing on these patients resulted in detection of rare CFI variants in 4.7% (n=22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of total patients recruited, 3.2% (n=15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen (RPD) was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.

    Genetic Determinants Highlight the Existence of Shared Etiopathogenetic Mechanisms Characterizing Age-Related Macular Degeneration and Neurodegenerative Disorders

    Front Neurol. 2021 May 31;12:626066.

    Claudia Strafella, Valerio Caputo, Andrea Termine, Carlo Fabrizio, Paola Ruffo, Saverio Potenza, Andrea Cusumano, Federico Ricci, Carlo Caltagirone, Emiliano Giardina, Raffaella Cascella

    PMID: 34135841 PMCID: PMC8200556 DOI: 10.3389/fneur.2021.626066

    Age-related macular degeneration (AMD) showed several processes and risk factors in common with neurodegenerative disorders (NDDs). The present work explored the existence of genetic determinants associated with AMD, which may provide insightful clues concerning its relationship with NDDs and their possible application into the clinical practice. In this study, 400 AMD patients were subjected to the genotyping analysis of 120 genetic variants by OpenArray technology. As the reference group, 503 samples representative of the European general population were utilized. Statistical analysis revealed the association of 23 single-nucleotide polymorphisms (SNPs) with AMD risk. The analysis of epistatic effects revealed that ARMS2, IL6, APOE, and IL2RA could contribute to AMD and neurodegenerative processes by synergistic modulation of the expression of disease-relevant genes. In addition, the bioinformatic analysis of the associated miRNA variants highlighted miR-196a, miR-6796, miR-6499, miR-6810, miR-499, and miR-7854 as potential candidates for counteracting AMD and neurodegenerative processes. Finally, this work highlighted the existence of shared disease mechanisms (oxidative stress, immune-inflammatory response, mitochondrial dysfunction, axonal guidance pathway, and synaptogenesis) between AMD and NDDs and described the associated SNPs as candidate biomarkers for developing novel strategies for early diagnosis, monitoring, and treatment of such disorders in a progressive aging population.


    Foveal regeneration after resolution of cystoid macular edema without and with internal limiting membrane detachment: presumed role of glial cells for foveal structure stabilization

    Int J Ophthalmol. 2021 Jun 18;14(6):818-833.

    Andreas Bringmann, Martin Karol, Jan Darius Unterlauft, Thomas Barth, Renate Wiedemann, Leon Kohen, Matus Rehak, Peter Wiedemann   

    PMID: 34150536 PMCID: PMC8165612 DOI: 10.18240/ijo.2021.06.06

    Aim: To document with spectral-domain optical coherence tomography the morphological regeneration of the fovea after resolution of cystoid macular edema (CME) without and with internal limiting membrane (ILM) detachment and to discuss the presumed role of the glial scaffold for foveal structure stabilization.

    Methods: A retrospective case series of 38 eyes of 35 patients is described. Of these, 17 eyes of 16 patients displayed foveal regeneration after resolution of CME, and 6 eyes of 6 patients displayed CME with ILM detachment. Eleven eyes of 9 patients displayed other kinds of foveal and retinal disorders associated with ILM detachment.

    Results: The pattern of edematous cyst distribution, with or without a large cyst in the foveola and preferred location of cysts in the inner nuclear layer or Henle fiber layer (HFL), may vary between different eyes with CME or in one eye during different CME episodes. Large cysts in the foveola may be associated with a tractional elevation of the inner foveal layers and the formation of a foveoschisis in the HFL. Edematous cysts are usually not formed in the ganglion cell layer. Eyes with CME and ILM detachment display a schisis between the detached ILM and nerve fiber layer (NFL) which is traversed by Müller cell trunks. ILM detachment was also found in single eyes with myopic traction maculopathy, macular pucker, full-thickness macular holes, outer lamellar holes, and glaucomatous parapapillary retinoschisis, and in 3 eyes with Müller cell sheen dystrophy (MCSD). As observed in eyes with MCSD, cellophane maculopathy, and macular pucker, respectively, fundus light reflections can be caused by different highly reflective membranes or layers: the thickened and tightened ILM which may or may not be detached from the NFL, the NFL, or idiopathic epiretinal membranes. In eyes with short single or multiple CME episodes, the central fovea regenerated either completely, which included the disappearance of irregularities of the photoreceptor layer lines and the reformation of a fovea externa, or with remaining irregularities of the photoreceptor layer lines.

    Conclusion: The examples of a complete regeneration of the foveal morphology after transient CME show that the fovea may withstand even large tractional deformations and has a conspicuous capacity of structural regeneration as long as no cell degeneration occurs. It is suggested that the regenerative capacity depends on the integrity of the threedimensional glial scaffold for foveal structure stabilization composed of Müller cell and astrocyte processes. The glial scaffold may also maintain the retinal structure after loss of most retinal neurons as in late-stage MCSD.