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    Research Update 562


    Evaluation of microaneurysms as predictors of therapeutic response to anti-VEGF therapy in patients with DME.

    PLoS One. 2022 Nov 28

    Hatano M, Higashijima F, Yoshimoto T, Ogata T, Ohta M, Kobayashi Y, Wakuta M, Yanai R, Kimura K.

    Administration of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is the first-line therapy for diabetic macular oedema (DME). However, some patients show no or insufficient response to repeated anti-VEGF injections. Therefore, it is necessary to identify factors that can predict this resistance against anti-VEGF treatment. Presence of microaneurysms (MAs) is a predictor of the development and progression of DME, but its relationship with the treatment response to the anti-VEGF agents is not well known. Therefore, we aimed to elucidate the relationship between the distribution of MAs and the response to anti-VEGF therapy in patients with DME. The number of MAs was measured before anti-VEGF therapy in each region using fluorescein angiography, indocyanine green angiography (IA), and optical coherence tomography angiography. Patients with DME were divided into the responder and non-responder groups after three loading phases. Differences in the distribution of MAs between the groups were investigated. Pre-treatment IA revealed more MAs in the nasal area in the non-responder group than in the responder group (10.7 ± 10.7 and 5.7 ± 5.7, respectively, in the nasal macula) (1.4 ± 2.1 and 0.4 ± 0.7, respectively, in the nasal fovea). Whereas, pre-treatment FA and OCTA could not reveal significantly difference between the groups. Detection of MAs in the nasal macula using pre-treatment IA may indicate resistance to anti-VEGF therapy. We recommend the clinicians confirm the presence of MAs in the nasal macula, as shown by IA, as a predictor of therapeutic response to anti-VEGF therapy in patients with treatment naive DME.

    DOI: 10.1371/journal.pone.0277920


    Antiplatelet and anticoagulant therapy in patients with submacular hemorrhage caused by neovascular age-related macular degeneration.

    Graefes Archive for Clinical and Experimental Ophthalmology. 2022 Nov 29

    Weber C, Bertelsmann M, Kiy Z, Stasik I, Holz FG, Liegl R.

    Purpose: Patients with extensive submacular hemorrhage (SMH) caused by age-related macular degeneration (AMD) have a poor visual prognosis despite surgical intervention. Systemic blood-thinning drugs, which are commonly prescribed in the same age group, are known to increase the risk of severe hemorrhage in many parts of the body. This study aimed to investigate whether systemic blood-thinning drugs have an impact on the severity of SMH and if there are differences between the different types of blood-thinning medication.

    Methods: We reviewed the medical records of patients who suffered from surgically treated SMH between 2020 and 2022. All patients received a full ophthalmologic examination upon presentation including best-corrected visual acuity (BCVA) and optical coherence tomography. Other characteristics that were recorded included size of hemorrhage, blood-thinning therapy, and reason for intake.

    Results: A total of 115 patients with a mean age of 82 years were included in this retrospective analysis. Eighty-three patients (72.2%) were on blood-thinning therapy. The mean size of SMH was 32.01 mm2. Mean BCVA at initial presentation was 1.63 logMAR and 1.59 logMAR 1 year after surgery. The size of SMH was significantly larger in patients on blood-thinning medication (35.92 mm2 vs. 21.91 mm2) (p = 0.001) and their BCVA postoperatively was worse with 1.68 logMAR compared to 1.30 logMAR after 1 year (p = 0.503). Patients with vitamin K antagonists had larger SMH size and worse outcomes regarding BCVA compared to direct oral anticoagulants.

    Conclusion: Blood thinners in patients with AMD affect the severity of SMH. Consequently, the indication for their intake should be critically evaluated.

    DOI: 10.1007/s00417-022-05885-2


    Effects of intravitreal injection of ranibizumab and aflibercept for branch retinal vein occlusion on the choroid: a retrospective study.

    BMC Ophthalmology. 2022 Nov 30

    Kishishita S, Sakanishi Y, Morita S, Matsuzawa M, Usui-Ouchi A, Ebihara N.

    Background: Macular edema is found in more than half of branch retinal vein occlusion (BRVO) cases, leading to visual loss in most of these cases. Intravitreal injection of anti-vascular endothelial growth factor is currently the standard treatment for macular edema due to BRVO (BRVO-ME). The difference in the effects of aflibercept and ranibizumab on the choroid in BRVO-ME is unknown. Therefore, we analyzed the effects of intravitreal injection of ranibizumab and aflibercept on BRVO-ME.

    Methods: We retrospectively observed changes in choroidal thickness in the subfoveal region in 36 patients with BRVO-ME who visited the Department of Ophthalmology at the Juntendo University Urayasu Hospital. The patients were treated with intravitreal injection of aflibercept or ranibizumab and followed up for 12 months or more.

    Results: The observed point bifurcated into the affected and non-affected sides 500 μm from the fovea. The central macular thickness (CMT) and subfoveal choroidal thickness (SFCT) were 564.2 ± 268.5 μm and 228.8 ± 50.1 μm, respectively, in the ranibizumab group (16 patients, 16 eyes) and 542.4 ± 172.5 μm and 246.1 ± 59.1 μm, respectively, in the aflibercept group (20 patients, 20 eyes). The changes in CMT at 12 months were 324.0 ± 262.6 μm and 326.55 ± 187.2 μm in the ranibizumab and aflibercept groups, respectively, with no significant difference (p = 0.97). Similarly, the changes in SFCT over 12 months were not significant between the groups (ranibizumab, 41.9 ± 33.0 μm; aflibercept, 43.8 ± 43.8 μm, p = 0.89).

    Conclusion: The effects of ranibizumab and aflibercept on choroidal thickness in BRVO-ME were the same regardless of the site. Although BRVO is a retinal disease, we hope that we can further explore the mechanism of BRVO-ME by observing changes in the choroid in the future.

    DOI: 10.1186/s12886-022-02685-4


    Macular and peripapillary retinal nerve fiber layer thinning in eyes with prediabetes in the elderly population: OTASSHA study.

    Graefes Archive for Clinical and Experimental Ophthalmology. 2022 Dec 1

    Toyama T, Kawai H, Hashimoto Y, Azuma K, Shiraya T, Numaga J, Obuchi S, Ueta T; OTASSHA Study Group.

    Purpose: To investigate retinal thickness parameters in the elderly with prediabetes mellitus (preDM) and type 2 DM without retinopathy (non-diabetic retinopathy [NDR]).

    Methods: This cross-sectional study included a total of 1273 eyes without retinal pathologies of 699 volunteers aged ≥ 65 years were included. The eyes were categorized into non-DM (606 eyes), preDM (480 eyes), and NDR (187 eyes) groups according to their HbA1c levels. Fundus photography, swept-source optical coherence tomography, and comprehensive systemic examination were conducted. The thicknesses of the retinal nerve fiber layer in the macula (mRNFL) and peripapillary (pRNFL), ganglion cell complex (GCC), and ganglion cell inner plexiform layer (GCIPL), as well as central subfield thickness (CST) and central foveal thickness (CFT) were investigated for their association with DM stage using linear mixed model.

    Results: A statistically significant thinning of mRNFL was observed in preDM vs. non-DM and in NDR vs. preDM in 3/6 sectors. A significant thinning of pRNFL was observed in preDM vs. non-DM and in NDR vs. preDM in 2/12 sectors. Such DM stage-dependent thinning of RNFL was observed mainly in the temporal and superior sectors. GCIPL and GCC were less sensitive to reflect DM-dependent inner retinal thinning. CST and CFT were not significantly associated with different DM stages.

    Conclusion: The thinning of mRNFL in the temporal and superior sectors might be a sensitive parameter associated with early neurodegeneration in preDM and NDR.

    DOI: 10.1007/s00417-022-05925-x


    The First-Year Variation in Central Retinal Thickness Predicts Legal Blindness in Patients with Neovascular Age-Related Macular Degeneration.

    Ophthalmic Research. 2022 Nov 25

    Guo Y, Wu J, Zheng X, Yin C, Wu Z.

    Background: Due to its progressive nature, early evaluation and timely prediction of legal blindness are important in patients with neovascular age-related macular degeneration (nAMD). We examined the association between early-stage variation in central retinal thickness (CRT) and long-term visual outcomes in patients with nAMD.

    Methods: We included 103 nAMD patients who were administered anti-vascular endothelial growth factor (anti-VGEF). Participants were considered qualified if they were: 1) 50 years and older, 2) treatment-naïve, 3) received standard anti-VEGF treatment and had complete baseline information. We further excluded patients with less than one-year follow-up data and those who experienced best-corrected visual acuity (BCVA) ≤35. Early-stage variability in CRT was measured as the first-year coefficient of variability (CV) of CRT. Patients were then classified into the high-variability and the low-variability groups according to the X-tile. A product-limit plot was used to demonstrate the differences and tested with the log-rank test. The association between first-year variability and visual outcomes was quantified using Cox regression models. Time-to-event primary endpoint was the overall visual preservation (OVP) rate, defined as the time from the first injection to legal blindness, i.e., BCVA ≤ 35 Early Treatment Diabetic Retinopathy Study (ETDRS) letters.

    Results: A threshold of 20% of first-year CV in CRT was used to categorized 76 qualified patients into high-variability (35, 46.1%) and low-variability (41, 53.9%). The 5- and 10-year OVPs for patients with high- vs. low-variability were 76% vs. 48%, and 59% vs. 22%, respectively. High early-stage CRT variability showed a significantly higher risk of legal blindness. Even after adjusting for the demographic and clinical features, the variability remained significant (HR=2.39, 95% CI: 1.20 to 4.78).

    Conclusions: First-year variability of CRT was predictive of long-term visual outcomes in patients with nAMD, and 20% of the variability could be used as a clinically convenient threshold to qualitatively classify patients into high- and low-variability groups. The current study is important for identifying high-risk populations and for long-term disease management.

    DOI: 10.1159/000528161


    An Evaluation of the Complement-Regulating Activities of Human Complement Factor H (FH) Variants Associated With Age-Related Macular Degeneration.

    Investigating Ophthalmology & Visual Science. 2022 Nov 1

    Biggs RM, Makou E, Lauder S, Herbert AP, Barlow PN, Katti SK.

    Purpose: Factor H (FH, encoded by CFH) prevents activation of the complement system’s alternative pathway (AP) on host tissues. FH impedes C3 convertase (C3bBb) formation, accelerates C3bBb decay, and is a cofactor for factor I (FI)-catalyzed C3b cleavage. Numerous CFH variants are associated with age-related macular degeneration (AMD), but their functional consequences frequently remain undetermined. Here, we conduct functional comparisons between a control version of FH (not AMD linked) and 21 AMD-linked FH variants.

    Methods: Recombinantly produced, untagged, full-length FH versions were assayed for binding to C3b and decay acceleration of C3bBb using surface-plasmon resonance, FI-cofactor activity using a fluorescent probe of C3b integrity, suppression of C5b-9 assembly on an AP-activating surface, and inhibition of human AP-mediated lysis of sheep erythrocytes.

    Results: All versions were successfully purified despite below-average yields for Arg2Thr, Arg53Cys, Arg175Pro, Arg175Gln, Ile221Val, Tyr402His, Pro503Ala, Arg567Gly, Gly1194Asp, and Arg1210Cys. Compared to control FH, Arg2Thr, Leu3Val, Ser58Ala, Asp90Gly, Asp130Asn, Gln400Lys, Tyr402His, Gly650Val, Ser890Ile, and Thr965Met showed minimal functional differences. Arg1210C, Arg53His, Arg175Gln, Gly1194Asp, Pro503Ala, Arg53Cys, Arg576Gly, and Arg175Pro (in order of decreasing efficacy) underperformed, while Ile221Val, Arg303Gln, and Arg303Trp were “marginal.” We newly identified variants toward the center of the molecule, Pro503Ala and Arg567Gly, as potentially pathogenic.

    Conclusions: Our approach could be extended to other variants of uncertain significance and to assays for noncanonical FH activities, aiming to facilitate selection of cohorts most likely to benefit from therapeutic FH. This is timely as recombinant therapeutic FH is in development for intravitreal treatment of AMD in patients with reduced FH functionality.

    DOI: 10.1167/iovs.63.12.30


    Exploring challenges to nutrition intervention adherence using COM-B model among patients with wet age-related macular degeneration: a qualitative study.

    BMJ Open. 2022 Nov 29

    Bian W, Wang Z, Wan J, Zhang F, Wu X, Li X, Luo Y.

    Objectives: To explore challenges to nutrition intervention adherence using the Capability, Opportunity and Motivation-Behaviour (COM-B) model among wet age-related macular degeneration (AMD) patients. These factors should be considered in the development of potential support and intervention programmes to address these problems.

    Design: A qualitative study was conducted with one-to-one and face-to-face interviews with wet AMD patients using a semi-structured question guide. Data were analysed based on COM-B model: capability (physical and psychological), opportunity (physical and social) and motivation (reflective and automatic).

    Setting: Southwest Hospital of Chongqing Province in China.

    Participants: A convenient and purposive sample of 24 wet AMD patients were recruited.

    Results: The themes and subthemes were identified: psychological capability: (1) insufficient knowledge of nutrition; (2) misconceptions about the disease and treatment; (3) knowledge conflict; physical capability: (1) physical restriction; (2) limited access to nutrition knowledge; physical opportunity: (1) communication between providers and patients; (2) health insurance and extra charges; (3) food environment; social opportunity: (1) stigma of disease; (2) family influence; reflective motivation: (1) self-efficacy; (2) attitude; (3) outcome expectancies; (4) lack of professional support; automatic motivation: (1) difficulties in changing eating habits; (2) mindset.

    Conclusion: Medical staff should pay much attention to the process of patients’ nutrition intervention. In addition, it is also necessary to develop professional and internet-based intervention to modify the dietary behaviour and improve the management skills of the patients.

    DOI: 10.1136/bmjopen-2022-064892


    Choriocapillaris flow deficit as a biomarker for diabetic retinopathy and diabetic macular edema: 3-year longitudinal cohort: Choriocapillaris flow predicts DR progression and DME development.

    American Journal of Ophthalmology. 2022 Nov 24

    Chen Y, Zhu Z, Cheng W, Bulloch G, Chen Y, Liao H, Li Y, Liang X, Huang W, He M, Wang W; GDES Group.

    Purpose: To investigate the relationship between choriocapillaris flow deficit percentage (CC FD%) by swept-source optical coherence tomography angiography (SS-OCTA) and 3-year risk of diabetic retinopathy (DR) progression and diabetic macular edema (DME) development. DESIGN: Prospective, observational cohort study.

    Methods: A total of 903 participants with type 2 diabetes mellitus (T2DM) without DR or with mild non-proliferative DR (NPDR) free of DME at baseline were followed up annually for 3 years. All participants underwent standard 7-field fundus photography and spectral-domain OCT. SS-OCTA was used for retinal and choriocapillaris imaging and 3 × 3 mm2 macular CC FD% was quantified. Univariate and multivariate logistic models were used to evaluate the association between CC FD% and two or more steps of DR progression and DME development. The additional predictive value of CC FD% for outcome events was assessed using C-statistic, net reclassification index (NRI), and integrated discrimination improvement index (IDI).

    Results: Over 3 years, 295 of 1805 eyes (16.34%) developed DR progression, and 118 eyes (6.54%) developed DME. A higher average CC FD% was correlated with DR progression (odds ratio [OR], 3.41 per SD increase, 95% confidence interval [CI]: 2.65-4.39, P<0.001) and DME development (OR, 1.37 per SD increase, 95% CI: 1.06-1.77, P=0.016) after adjusting for confounders. In the ETDRS regions, increased CC FD% in all fields was associated with DR progression; however, increased CC FD% in the inferior field was associated with DME development. Compared with the models based on established risk factors, the addition of average CC FD% significantly improved the C-statistics for DR progression (0.712 to 0.777, P<0.001) and DME occurrence (0.743 to 0.773, P=0.044). The estimated NRIs and IDIs (all >0) indicated that the addition of CC FD% led to a significant improvement in the discriminative performance for endpoints.

    Conclusion: CC FD% is independently associated with DR progression and DME development in the Chinese T2DM population and provides incremental predictive value beyond traditional risk factors and retinal microvascular parameters. Further inclusion of CC FD% in DR prediction models helps guide population-based screening and personalized management.

    DOI: 10.1016/j.ajo.2022.11.018


    Acute retinal ischaemia associated with paracentral acute middle maculopathy detected on multimodal imaging: a premonitory sign of severe carotid occlusive disease.

    BMJ Case Reports. 2022 Nov 28

    Antaki F, Milad D, Hamel T.

    A man in his 60s presented with a subacute paracentral scotoma and preserved visual acuity in the left eye. He was found to have a very subtle area of deep retinal whitening at the macula and multiple retinal cholesterol emboli. Optical coherence tomography (OCT) with En face imaging revealed globular paracentral acute middle maculopathy (PAMM). A diagnosis of PAMM associated with branch artery occlusion was made and the patient was immediately transferred to the nearest stroke centre. Investigations revealed severe carotid occlusive disease for which the patient underwent carotid endarterectomy. Paracentral scotomas in patients with little clinical findings on fundus examination should raise the suspicion for PAMM, which is easily identifiable on OCT. Eye care professionals must recognise PAMM as a possible sign of acute retinal arterial ischaemia-an ocular and systemic emergency that requires immediate referral to specialised stroke centres.

    DOI: 10.1136/bcr-2022-252266