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10 pages, 509 KiB

Open AccessArticle

Role of Novel Inflammatory Factors in Central Retinal Vein Occlusion with Macular Edema

by Kanako Yasuda, Hidetaka Noma, Tatsuya Mimura, Ryota Nonaka, Shotaro Sasaki, Akemi Ofusa and Masahiko Shimura

Medicina 2024, 60(1), 4; https://doi.org/10.3390/medicina60010004 - 19 Dec 2023

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Abstract

Background and Objectives: To investigate associations among the aqueous humor levels of novel inflammatory factors, including FMS-related tyrosine kinase 3 ligand (Flt-3L), fractalkine, CXC chemokine ligand 16 (CXCL-16), and endocan-1; the severity of macular edema in central retinal vein occlusion (CRVO); and [...] Read more.

Background and Objectives: To investigate associations among the aqueous humor levels of novel inflammatory factors, including FMS-related tyrosine kinase 3 ligand (Flt-3L), fractalkine, CXC chemokine ligand 16 (CXCL-16), and endocan-1; the severity of macular edema in central retinal vein occlusion (CRVO); and the prognosis of CRVO with macular edema after antivascular endothelial growth factor (VEGF) therapy. Materials and Methods: Aqueous humor was obtained during anti-VEGF treatment with intravitreal ranibizumab injection (IRI) in patients with CRVO and macular edema (n = 19) and during cataract surgery in patients with cataracts (controls, n = 20), and the levels of VEGF and novel inflammatory factors were measured. Macular edema was evaluated by central macular thickness (CMT) and neurosensory retinal thickness (TNeuro), and improvement was evaluated by calculating the percentage change in CMT and TNeuro from before to 1 month after IRI. Results: The levels of VEGF and the novel inflammatory factors were significantly higher in the CRVO group, and the levels of Flt-3L, CXCL-16, and endocan-1 were significantly correlated with each other and with the aqueous flare value. Baseline levels of Flt-3L, CXCL-16, and endocan-1 had a significantly negative correlation with the change in CMT, and the baseline level of CXCL-16 was significantly negatively correlated with the change in TNeuro. Conclusions: Relations among novel inflammatory factors should be further investigated. These findings may help improve understanding of macular edema in CRVO patients and aid the development of new treatments targeting novel inflammatory factors. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

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7 pages, 294 KiB

Open AccessArticle

Faricimab for Diabetic Macular Edema in Patients Refractory to Ranibizumab or Aflibercept

by Hiromi Ohara, Yosuke Harada, Tomona Hiyama, Ayako Sadahide, Akira Minamoto and Yoshiaki Kiuchi

Medicina 2023, 59(6), 1125; https://doi.org/10.3390/medicina59061125 - 11 Jun 2023

Cited by 1 | Viewed by 2698

Abstract

Background and Objectives: Faricimab is the first intravitreal injection of vascular endothelial growth factor-A and angiopoietin-2 bispecific monoclonal antibody. Here, we evaluate the functional and anatomical outcomes of faricimab treatment in patients with diabetic macular edema (DME) that was refractory to ranibizumab [...] Read more.

Background and Objectives: Faricimab is the first intravitreal injection of vascular endothelial growth factor-A and angiopoietin-2 bispecific monoclonal antibody. Here, we evaluate the functional and anatomical outcomes of faricimab treatment in patients with diabetic macular edema (DME) that was refractory to ranibizumab or aflibercept. Materials and Methods: We performed a retrospective, observational, consecutive-case study of patients who had DME that was refractory to treatment with ranibizumab or aflibercept and were treated with faricimab between July 2022 and January 2023 under a pro re nata regimen. All the participants were followed for ≥4 months after the initiation of faricimab. The primary outcome was a recurrence interval of ≥12 weeks, and the secondary outcomes were the changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT). Results: We analyzed 18 eyes of 18 patients. The mean recurrence interval of previous anti-VEGF injection was 5.8 ± 2.5 weeks, which was significantly extended to 10.8 ± 4.9 weeks (p = 0.0005) by the switch to faricimab. Eight patients (44.4%) achieved a recurrence interval of ≥12 weeks. A history of subtenon injection of triamcinolone acetonide (p = 0.0034) and the presence of disorganization of the retinal inner layers (p = 0.0326) were found to be significantly associated with a recurrence interval of <12 weeks. The mean BCVAs were 0.23 ± 0.28 logMAR and 0.19 ± 0.23 logMAR, and the mean CMTs were 473.8 ± 222.0 µm and 381.3 ± 219.4 µm at baseline and 4 months, respectively, but these changes were not statistically significant. None of the patients experienced serious adverse events. Conclusions: Faricimab may extend the treatment interval for patients with DME that is refractory to ranibizumab or aflibercept. DME previously treated with the subtenon injection of triamcinolone acetonide or associated with disorganization of the retinal inner layers may be less likely to be associated with a longer recurrence interval after switching to faricimab. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

13 pages, 3220 KiB

Open AccessFeature PaperArticle

Effects of Intravitreal Ranibizumab Injection on Peripheral Retinal Microcirculation and Cytokines in Branch Retinal Vein Occlusion with Macular Edema

by Kanako Yasuda, Hidetaka Noma, Tatsuya Mimura, Ryota Nonaka, Shotaro Sasaki, Noboru Suganuma and Masahiko Shimura

Medicina 2023, 59(6), 1053; https://doi.org/10.3390/medicina59061053 - 30 May 2023

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Abstract

Background and Objectives: To investigate peripheral blood flow in retinal vessels and vessel diameters after intravitreal ranibizumab injection (IRI) and the relationship between these parameters and cytokines in branch retinal vein occlusion (BRVO) with macular edema. Materials and Methods: We assessed [...] Read more.

Background and Objectives: To investigate peripheral blood flow in retinal vessels and vessel diameters after intravitreal ranibizumab injection (IRI) and the relationship between these parameters and cytokines in branch retinal vein occlusion (BRVO) with macular edema. Materials and Methods: We assessed relative flow volume (RFV) and the width of the main and branch retinal arteries and veins in the occluded and non-occluded regions before and after IRI in 37 patients with BRVO and macular edema. Measurements were made using laser speckle flowgraphy (LSFG). When performing IRI, we obtained samples of aqueous humor and analyzed them using the suspension array method to evaluate vascular endothelial growth factor (VEGF), placental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-6, IL-8, and interferon-inducible 10-kDa protein (IP-10). Results: In both retinal regions, before and after IRI, the RFV in the main artery and vein showed a significant correlation with the summed RFV in the respective branch vessels 1 and 2. In the occluded region, the RFV in the main vein was significantly negatively correlated with MCP-1, PDGF-AA, IL-6, and IL-8; the RFV in branch vein 1 was significantly negatively correlated with PlGF, MCP-1, IL-6, and IL-8; PDGF-AA was significantly negatively correlated with the width of the main and branch veins; and the RFVs of the main artery and vein decreased significantly from before to 1 month after IRI. Conclusions: Contrary to expectations, the study found that anti-VEGF therapy does not affect RFV in arteries and veins in patients with BRVO and macular edema. Furthermore, retinal blood flow is poor in patients with high MCP-1, IL-6, and IL-8. Finally, high PDGF-AA may result in smaller venous diameters and reduced retinal blood flow. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

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9 pages, 746 KiB

Open AccessArticle

Clinical Application of Intravitreal Aflibercept Injection for Diabetic Macular Edema Comparing Two Loading Regimens

by Yoo-Ri Chung, Kyung Ho Lee and Kihwang Lee

Medicina 2023, 59(3), 558; https://doi.org/10.3390/medicina59030558 - 12 Mar 2023

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Abstract

Background and Objectives: We investigated and compared the efficacy of three and five monthly loading regimens of an intravitreal aflibercept injection (IVA) in patients with diabetic macular edema (DME). Materials and Methods: This was a retrospective study that included patients diagnosed [...] Read more.

Background and Objectives: We investigated and compared the efficacy of three and five monthly loading regimens of an intravitreal aflibercept injection (IVA) in patients with diabetic macular edema (DME). Materials and Methods: This was a retrospective study that included patients diagnosed with DME and treated with an either three or five monthly aflibercept loading regimen from July 2018 to March 2022. Information on clinical characteristics and changes in the central retinal thickness (CRT) were obtained from medical records. Results: In total, 44 eyes of 44 patients with DME treated with IVA were included in this study, with 30 eyes treated with 3-monthly loadings (three-loading group) and 14 eyes with 5-monthly loadings (five-loading group). The mean CRT significantly decreased from the baseline one month after loading in both the three-loading and five-loading groups (p < 0.001). Four cases were refractory to treatment in the three-loading group, while there were no cases of refractory DME in the five-loading group. The stability rate was significantly higher in the five-loading group at three months after loading (p = 0.033). Conclusions: Five-monthly loading regimens of IVA might be favorable for DME considering the rate of refractory cases, stable duration, and the importance of early responsiveness to IVA in DME. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

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9 pages, 4416 KiB

Open AccessArticle

Correlation between Morphological Characteristics of Macular Edema and Visual Acuity in Young Patients with Idiopathic Intermediate Uveitis

by Ludovico Iannetti, Fabio Scarinci, Ludovico Alisi, Marta Armentano, Lorenzo Sampalmieri, Maurizio La Cava and Magda Gharbiya

Medicina 2023, 59(3), 529; https://doi.org/10.3390/medicina59030529 - 08 Mar 2023

Cited by 1 | Viewed by 1283

Abstract

Background and Objectives: Macular edema (ME) is a common complication of intermediate uveitis (IU). It is often responsible for a decrease in visual acuity (VA). Three distinct patterns of macular edema have been described in intermediate uveitis, namely, cystoid macular edema (CME), diffuse [...] Read more.

Background and Objectives: Macular edema (ME) is a common complication of intermediate uveitis (IU). It is often responsible for a decrease in visual acuity (VA). Three distinct patterns of macular edema have been described in intermediate uveitis, namely, cystoid macular edema (CME), diffuse macular edema (DME), and serous retinal detachment (SRD). The current study aims to describe the characteristics of macular edema in young patients with idiopathic intermediate uveitis and to correlate its features with VA using spectral domain optical coherence tomography (SD-OCT). Materials and Methods: A total of 27 eyes from 18 patients with idiopathic IU complicated by ME were included in this retrospective study. All patients underwent SD-OCT; data were gathered at the onset of ME. Best-corrected VA (BCVA) was correlated with the morphological features of ME. Results: BCVA was negatively correlated with Ellipsoid Zone (EZ) disruption (p = 0.00021), cystoid pattern (p = 0.00021), central subfield thickness (CST) (p < 0.001), and serous retinal detachment (0.037). Conclusions: In ME secondary to idiopathic IU, VA negatively correlates with Ellipsoid Zone disruption and increases in CST. Moreover, vision is influenced by the presence of cysts in the inner nuclear and outer nuclear layers and by the neuroepithelium detachment. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

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Review

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10 pages, 1162 KiB

Open AccessReview

How Can Artificial Intelligence Be Implemented Effectively in Diabetic Retinopathy Screening in Japan?

by Ryo Kawasaki

Medicina 2024, 60(2), 243; https://doi.org/10.3390/medicina60020243 - 30 Jan 2024

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Abstract

Diabetic retinopathy (DR) is a major microvascular complication of diabetes, affecting a substantial portion of diabetic patients worldwide. Timely intervention is pivotal in mitigating the risk of blindness associated with DR, yet early detection remains a challenge due to the absence of early [...] Read more.

Diabetic retinopathy (DR) is a major microvascular complication of diabetes, affecting a substantial portion of diabetic patients worldwide. Timely intervention is pivotal in mitigating the risk of blindness associated with DR, yet early detection remains a challenge due to the absence of early symptoms. Screening programs have emerged as a strategy to address this burden, and this paper delves into the role of artificial intelligence (AI) in advancing DR screening in Japan. There are two pathways for DR screening in Japan: a health screening pathway and a clinical referral path from physicians to ophthalmologists. AI technologies that realize automated image classification by applying deep learning are emerging. These technologies have exhibited substantial promise, achieving sensitivity and specificity levels exceeding 90% in prospective studies. Moreover, we introduce the potential of Generative AI and large language models (LLMs) to transform healthcare delivery, particularly in patient engagement, medical records, and decision support. Considering the use of AI in DR screening in Japan, we propose to follow a seven-step framework for systematic screening and emphasize the importance of integrating AI into a well-designed screening program. Automated scoring systems with AI enhance screening quality, but their effectiveness depends on their integration into the broader screening ecosystem. LLMs emerge as an important tool to fill gaps in the screening process, from personalized invitations to reporting results, facilitating a seamless and efficient system. However, it is essential to address concerns surrounding technical accuracy and governance before full-scale integration into the healthcare system. In conclusion, this review highlights the challenges in the current screening pathway and the potential for AI, particularly LLM, to revolutionize DR screening in Japan. The future direction will depend on leadership from ophthalmologists and stakeholders to address long-standing challenges in DR screening so that all people have access to accessible and effective screening. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

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19 pages, 2470 KiB

Open AccessReview

The Role of Laser Photocoagulation in Treating Diabetic Macular Edema in the Era of Intravitreal Drug Administration: A Descriptive Review

by Miho Nozaki, Ryota Ando, Toshiya Kimura, Fusae Kato and Tsutomu Yasukawa

Medicina 2023, 59(7), 1319; https://doi.org/10.3390/medicina59071319 - 17 Jul 2023

Cited by 2 | Viewed by 2735

Abstract

Background and Objectives: This study aimed to elucidate the role of laser photocoagulation therapy in the treatment of diabetic macular edema (DME) as an alternative to, or in conjunction with, the first-line treatment, anti-vascular endothelial growth factor (VEGF). Materials and Methods: [...] Read more.

Background and Objectives: This study aimed to elucidate the role of laser photocoagulation therapy in the treatment of diabetic macular edema (DME) as an alternative to, or in conjunction with, the first-line treatment, anti-vascular endothelial growth factor (VEGF). Materials and Methods: A comprehensive literature search to identify studies that evaluated the efficacy of laser photocoagulation therapy in the management of DME was performed. The relevant findings of the efficacy of focal/grid laser therapy from data in randomized, controlled trials were synthesized, and the potential of new laser technologies, such as navigated laser systems, pattern scan lasers, and subthreshold lasers, was explored. The usefulness of multimodal imaging-guided laser therapy was also evaluated, with a focus on the potential contribution to anti-VEGF therapy. Results: Focal laser photocoagulation targeting microaneurysms remains an effective therapeutic approach to chronic refractory edema, despite the widespread use of anti-VEGF therapy. To achieve the best possible treatment outcomes, precise identification of microaneurysms is essential. This requires the use of multimodal imaging-guided, highly accurate, minimally invasive coagulation techniques. Subthreshold laser therapy can also reduce the frequency of anti-VEGF injections and minimize treatment burden. Conclusions: Further studies are needed to determine the optimal timing and settings for laser photocoagulation therapy and the potential of new laser technologies in the management of DME. Nevertheless, laser photocoagulation therapy plays an important role in the management of DME, in conjunction with anti-VEGF therapy. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

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18 pages, 9136 KiB

Open AccessReview

Pathological Neurovascular Unit Mapping onto Multimodal Imaging in Diabetic Macular Edema

by Tomoaki Murakami, Kenji Ishihara, Noriko Terada, Keiichi Nishikawa, Kentaro Kawai and Akitaka Tsujikawa

Medicina 2023, 59(5), 896; https://doi.org/10.3390/medicina59050896 - 07 May 2023

Cited by 2 | Viewed by 1817

Abstract

Diabetic retinopathy is a form of diabetic microangiopathy, and vascular hyperpermeability in the macula leads to retinal thickening and concomitant reduction of visual acuity in diabetic macular edema (DME). In this review, we discuss multimodal fundus imaging, comparing the pathogenesis and interventions. Clinicians [...] Read more.

Diabetic retinopathy is a form of diabetic microangiopathy, and vascular hyperpermeability in the macula leads to retinal thickening and concomitant reduction of visual acuity in diabetic macular edema (DME). In this review, we discuss multimodal fundus imaging, comparing the pathogenesis and interventions. Clinicians diagnose DME using two major criteria, clinically significant macular edema by fundus examination and center-involving diabetic macular edema using optical coherence tomography (OCT), to determine the appropriate treatment. In addition to fundus photography, fluorescein angiography (FA) is a classical modality to evaluate morphological and functional changes in retinal capillaries, e.g., microaneurysms, capillary nonperfusion, and fluorescein leakage. Recently, optical coherence tomography angiography (OCTA) has allowed us to evaluate the three-dimensional structure of the retinal vasculature and newly demonstrated that lamellar capillary nonperfusion in the deep layer is associated with retinal edema. The clinical application of OCT has accelerated our understanding of various neuronal damages in DME. Retinal thickness measured by OCT enables us to quantitatively assess therapeutic effects. Sectional OCT images depict the deformation of neural tissues, e.g., cystoid macular edema, serous retinal detachment, and sponge-like retinal swelling. The disorganization of retinal inner layers (DRIL) and foveal photoreceptor damage, biomarkers of neurodegeneration, are associated with visual impairment. Fundus autofluorescence derives from the retinal pigment epithelium (RPE) and its qualitative and quantitative changes suggest that the RPE damage contributes to the neuronal changes in DME. These clinical findings on multimodal imaging help to elucidate the pathology in the neurovascular units and lead to the next generation of clinical and translational research in DME. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

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11 pages, 4034 KiB

Open AccessReview

Role of Microaneurysms in the Pathogenesis and Therapy of Diabetic Macular Edema: A Descriptive Review

by Yoshihiro Takamura, Yutaka Yamada and Masaru Inatani

Medicina 2023, 59(3), 435; https://doi.org/10.3390/medicina59030435 - 22 Feb 2023

Cited by 4 | Viewed by 3434

Abstract

Background and Objectives: This study aims to elucidate the role of microaneurysms (MAs) in the pathogenesis and treatment of diabetic retinopathy (DR) and diabetic macular edema (DME), the major causes of acquired visual impairment. Materials and Methods: We synthesized the relevance of findings [...] Read more.

Background and Objectives: This study aims to elucidate the role of microaneurysms (MAs) in the pathogenesis and treatment of diabetic retinopathy (DR) and diabetic macular edema (DME), the major causes of acquired visual impairment. Materials and Methods: We synthesized the relevance of findings on the clinical characteristics, pathogenesis, and etiology of MAs in DR and DME and their role in anti-vascular endothelial growth factor (VEGF) therapy. Results: MAs, a characteristic feature in DR and DME, can be detected by fluorescein angiography, optical coherence tomography (OCT) and OCT angiography. These instrumental analyses demonstrated a geographic and functional association between MA and ischemic areas. MA turnover, the production and loss of MA, reflects the activity of DME and DR. Several cytokines are involved in the pathogenesis of MAs, which is characterized by pericyte loss and endothelial cell proliferation in a VEGF-dependent or -independent manner. Ischemia and MAs localized in the deep retinal layers are characteristic of refractory DME cases. Even in the current anti-VEGF era, laser photocoagulation targeting MAs in the focal residual edema is still an effective therapeutic tool, but it is necessary to be creative in accurately identifying the location of MAs and performing highly precise and minimally invasive coagulation. Conclusions: MAs play a distinctive and important role in the pathogenesis of the onset, progression of DR and DME, and response to anti-VEGF treatment. Further research on MA is significant not only for understanding the pathogenesis of DME but also for improving the effectiveness of treatment. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

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15 pages, 3593 KiB

Open AccessReview

Laser-Induced Porcine Model of Experimental Retinal Vein Occlusion: An Optimized Reproducible Approach

by Mads Odgaard Mæng, Nirrooja Roshanth, Anders Kruse, Jonas Ellegaard Nielsen, Benedict Kjærgaard, Bent Honoré, Henrik Vorum and Lasse Jørgensen Cehofski

Medicina 2023, 59(2), 243; https://doi.org/10.3390/medicina59020243 - 27 Jan 2023

Cited by 3 | Viewed by 1623

Abstract

Retinal vein occlusion (RVO) is a frequent visually disabling condition. The management of RVO continues to challenge clinicians. Macular edema secondary to RVO is often recurrent, and patients typically require intravitreal injections for several years. Understanding molecular mechanisms in RVO is a key [...] Read more.

Retinal vein occlusion (RVO) is a frequent visually disabling condition. The management of RVO continues to challenge clinicians. Macular edema secondary to RVO is often recurrent, and patients typically require intravitreal injections for several years. Understanding molecular mechanisms in RVO is a key element in improving the treatment of the condition. Studying the molecular mechanisms in RVO at the retinal level is possible using animal models of experimental RVO. Most studies of experimental RVO have been sporadic, using only a few animals per experiment. Here, we report on 10 years of experience of the use of argon laser-induced experimental RVO in 108 porcine eyes from 65 animals, including 65 eyes with experimental branch retinal vein occlusion (BRVO) and 43 eyes with experimental central retinal vein occlusion (CRVO). Reproducibility and methods for evaluating and controlling ischemia in experimental RVO are reviewed. Methods for studying protein changes in RVO are discussed in detail, including proteomic analysis, Western blotting, and immunohistochemistry. Experimental RVO has brought significant insights into molecular changes in RVO. Testing intravitreal interventions in experimental RVO may be a significant step in developing personalized therapeutic approaches for patients with RVO. Full article

(This article belongs to the Special Issue Macular Edema: Pathogenesis, Diagnosis and Therapies)

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