Anti-VEGF therapy for the long-term management of diabetic macular edema: a treat-to-target strategy based on macular morphology.

In an aging population, the prevalence and burden of diabetes mellitus, diabetic retinopathy, and vision-threatening diabetic macular edema (DME) are only expected to rise around the world. Similarly to other complications of diabetes mellitus, DME requires long-term management. This article aims to review the current challenges associated with the long-term management of DME, opportunities to improve outcomes for patients, and to develop a treat-to-target strategy based on macular morphology. At present, intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for the management of DME; however, best-achievable vision outcomes with treatment are reliant on frequent injections and close monitoring, which are difficult to maintain in current clinical practice because of the burden this imposes on patients. Achieving and maintaining good vision with treatment are the most important factors for patients with DME. Landmark trials have shown that vision gains with anti-VEGF therapy are typically accompanied by anatomical improvements (e.g., reductions in retinal thickness); therefore, multimodal imaging measures of macular morphology are often used in patients with DME to guide real-world treatment decisions. We would like to propose a hypothetical treat-to-target algorithm to guide physicians on treatment strategies for the long-term management of DME. Alternative measures of retinal fluid (e.g., persistence, stability, location) may be stronger predictors of visual acuity in DME, although further research is required to confirm whether alternate quantifiable biomarkers such as subretinal fluid and intraretinal fluid volumes can be used as a biomarker of clinical improvement. Identifying novel biomarkers and treatments that target neuroinflammation and neurodegeneration, improving patient-physician communication around treatment adherence, and using treat-to-target measures may help to ensure that the long-term benefits of treatment are realized.

Heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation.

AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by neuroinflammation that drives neuronal and vascular degenerative pathology, which in many individuals can lead to retinal ischaemia and neovascularisation. Infiltrating macrophages and activated retina-resident microglia have been implicated in the progression of diabetic retinopathy, although the distinct roles of these immune cells remain ill-defined. Our aim was to clarify the distinct roles of macrophages/microglia in the pathogenesis of proliferative ischaemic retinopathies. METHODS: Murine oxygen-induced retinopathy is commonly used as a model of ischaemia-induced proliferative diabetic retinopathy (PDR). We evaluated the phenotype macrophages/microglia by immunostaining, quantitative real-time RT-PCR (qRT-PCR), flow cytometry and scRNA-seq analysis. In clinical imaging studies of diabetic retinopathy, we used optical coherence tomography (OCT) and OCT angiography. RESULTS: Immunostaining, qRT-PCR and flow cytometry showed expression levels of M1-like macrophages/microglia markers (CD80, CD68 and nitric oxide synthase 2) and M2-like macrophages/microglia markers (CD206, CD163 and macrophage scavenger receptor 1) were upregulated in areas of retinal ischaemia and around neo-vessels, respectively. scRNA-seq analysis of the ischaemic retina revealed distinct ischaemia-related clusters of macrophages/microglia that express M1 markers as well as C-C chemokine receptor 2. Inhibition of Rho-kinase (ROCK) suppressed CCL2 expression and reduced CCR2-positive M1-like macrophages/microglia in areas of ischaemia. Furthermore, the area of retinal ischaemia was reduced by suppressing blood macrophage infiltration not only by ROCK inhibitor and monocyte chemoattractant protein-1 antibody but also by GdCl3. Clinical imaging studies of diabetic retinopathy using OCT indicated potential involvement of macrophages/microglia represented by hyperreflective foci in areas of reduced perfusion. CONCLUSIONS/INTERPRETATION: These results collectively indicated that heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation in retinal vascular diseases including diabetic retinopathy. This adds important new information that could provide a basis for a more targeted, cell-specific therapeutic approach to prevent progression to sight-threatening PDR.

A Case of Congenital Idiopathic Enlargement of Extraocular Muscles.

The purpose of this case report is to report a case of congenital idiopathic enlargement of extraocular muscles. A four-month-old girl showed limitation of adduction and supraduction in the right eye. A computerized axial tomography (CAT) scan revealed hypertrophy of the lateral rectus muscle and inferior rectus muscle of the right eye. Thyroid hormone and antibody levels were normal. No inflammatory findings on magnetic resonance imaging (MRI). A traction test under general anesthesia revealed a strong limitation of supraduction and a mild limitation of adduction. Therefore, the inferior rectus muscle was recessed 4.5 mm at the age of six months. A partial biopsy of the inferior rectus showed no inflammatory cell infiltration. After the first surgery, the patient's limitation of supraduction improved, but the limitation of adduction persisted. So, a 5 mm recession of the right lateral rectus muscle was added at one year and one month. However, the hypertropia of the sound eye became stronger after treatment of amblyopia. Because of the strong limitation of supraduction, tenotomy of the inferior rectus was performed at the age of six years. Postoperatively, no impairment of infraduction occurred, and the limitation of supraduction was mildly improved. Since the findings on MRI were not changed through our observation period, we concluded that the patient had idiopathic external ophthalmoplegia.

Human ocular thelaziasis with genetic analysis in Niigata Prefecture, Japan: A case report on an emerging zoonosis.

Purpose: We report the clinical findings and molecular identification of ocular Thelazia callipaeda from Niigata Prefecture in the Hokuriku area of Japan during winter. Observations: A 77-year-old male visited an ophthalmology clinic in Niigata Prefecture in January 2022 after a 2-week-duration of a conjunctival injection in the left eye and foreign body sensation. Slit-lamp microscopy revealed 11 active nematodes in the left conjunctival sac. Morphological characteristics included longer female body length than male, buccal cavity lacking teeth and lips, and serrated striations along the body surface. The specimens were determined to be T. callipaeda. Genetic analysis of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene revealed an h9 haplotype. Conclusions and Importance: T. callipaeda infection, especially the h9 haplotype, commonly occurs in western Japan owing to its higher incidence in warmer climates, suggesting the origin of the case. Here, we report a human case of Thelaziasis diagnosed in a cold region of Japan (the Hokuriku area) during winter. This human case of T. callipaeda infection from a cold, previously unassociated region, raises concerns about the potential geographical widening of its distribution, and further investigation may be warranted to prevent its spread.

Optimal cutoff value of the dry eye-related quality-of-life score for diagnosing dry eye disease.

This retrospective study aimed to determine the optimal cutoff values of the Dry Eye-Related Quality-of-Life Score (DEQS) questionnaire for diagnosing dry eye disease (DED) and classifying DED severities. Participants completed the DEQS questionnaire, the Japanese version of the Ocular Surface Disease Index (J-OSDI) questionnaire, and DED examinations. DED was diagnosed according to the 2016 Asia Dry Eye Society diagnostic criteria based on DED symptoms (J-OSDI ≥ 13 points) and tear film breakup time ≤ 5 s. Receiver operating characteristic (ROC) analysis was used to calculate the optimal cutoff values of the DEQS summary score for detecting DED and grading its severity. Among 427 patients, 296 (69.3%) and 131 (30.7%) were diagnosed with DED and non-DED, respectively. ROC analysis determined an optimal cutoff value of 15.0 points for DED diagnosis, with 83.5% sensitivity, 87.0% specificity, and an area under the curve of 0.915. The positive and negative predictive values for DEQS ≥ 15.0 points were 93.6% and 69.9%, respectively. DEQS cutoff values of 15.0, 20.0, and 26.8 points could be accepted for severity classification of DED subjective symptoms in clinical use and represent mild, moderate, and severe DED, respectively. Conclusively, the optimal cutoff values of DEQS enable DED detection and subjective symptom severity classification.

Retinal neurovascular alteration in type 2 diabetes with renal impairment in association with systemic arterial stiffness.

BACKGROUND: Diabetic retinopathy (DR) patients should be alert for subclinical macroangiopathy. We aimed to investigate the association between retinal neurovascular alteration and systemic arterial stiffness in type 2 diabetes mellitus (type 2 DM) patients with varying degrees of renal impairment. METHODS: The study included 170 patients with confirmed diagnosis of type 2 DM aged ≥18 years old. Renal function was assessed by estimated glomerular filtration rate (eGFR). Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV) and ankle brachial index (ABI). Retinal neurovascular parameters were derived from Optical Coherence Tomography (OCT)/OCT-Angiography, represented by vessel density (VD Central, Inner, Outer, Full), foveal avascular zone (FAZ area and FAZ perimeter) of the superficial capillary plexus, the average of macular ganglion cell-inner plexiform layer thickness (ave mGC-IPLt) and the average of retinal nerve fiber layer thickness (aveRNFLt). The association between variables among the groups (according to renal function, diabetic retinopathy (DR) severity, and arterial stiffness categories) were analyzed by regression analysis with multiple hypothesis testing commands. RESULTS: Out of the 265 eyes, the mean DM duration and HbA1c were 6.21 ± 6.37 years and 8.44 ± 2.06% respectively. While the mean of eGFR, baPWV and ABI were 66.78 ± 32.80 ml/min/1.73m2, 15.49 ± 3.07 m/s, and 1.05 ± 0.12, respectively. Patients with more severe renal impairment demonstrated longer DM duration (p < 0.001), higher baPWV (p < 0.0001), and retinal vascular alteration. Proliverative DR group showed the lowest eGFR (p < 0.0001), highest baPWV (p < 0.0001), and retinal neurovascular changes. Significantly lower eGFR and retinal vascular alteration were found in the baPWV > 14 group. Some neurovascular parameters were significantly negatively correlated with baPWV; moreover, retinal neurovascular changes were also noted in the abnormal ABI group. CONCLUSIONS: The strong association between changes in the retinal neurovascular system, DR severity, renal impairment, and arterial stiffness in type 2 DM was confirmed. Patients with more severe renal impairment had higher levels of arterial stiffness, more severe DR and retinal neurovascular alteration. Retinal neurovascular changes seen in OCT/OCTA might mimic renal microvascular alteration and systemic arterial stiffness. Therefore, assessment of baPWV and OCT/OCTA should be integrated in DR screening to enhance cardiovascular risk stratification and prognosis as well as to provide clinically useful early identification of subclinical micro- and macrovascular alterations.

A nerve-goblet cell association promotes allergic conjunctivitis through rapid antigen passage.

The penetration of allergens through the epithelial layer is the initial step in the development of allergic conjunctivitis. Although pollinosis patients manifest symptoms within minutes after pollen exposure, the mechanisms of the rapid transport of the allergens remain unclear. In the present study, we found that the instillation of pollen shells rapidly induces a large number of goblet cell-associated antigen passages (GAPs) in the conjunctiva. Antigen acquisition by stromal cells, including macrophages and CD11b+ dendritic cells, correlated with surface GAP formation. Furthermore, a substantial amount of antigen was transported to the stroma during the first 10 minutes of pollen exposure, which was sufficient for the full induction of an allergic conjunctivitis mouse model. This inducible, rapid GAP formation and antigen acquisition were suppressed by topical lidocaine or trigeminal nerve ablation, indicating that the sensory nervous system plays an essential role. Interestingly, pollen shell-stimulated GAP formation was not suppressed by topical atropine, suggesting that the conjunctival GAPs and intestinal GAPs are differentially regulated. These results identify pollen shell-induced GAP as a therapeutic target for allergic conjunctivitis.

Integrating human iPSC-derived macrophage progenitors into retinal organoids to generate a mature retinal microglial niche.

In the retina, microglia are resident immune cells that are essential for development and function. Retinal microglia play a central role in mediating pathological degeneration in diseases such as glaucoma, retinitis pigmentosa, age-related neurodegeneration, ischemic retinopathy, and diabetic retinopathy. Current models of mature human retinal organoids (ROs) derived from iPS cell (hiPSC) do not contain resident microglia integrated into retinal layers. Increasing cellular diversity in ROs by including resident microglia would more accurately represent the native retina and better model diseases in which microglia play a key role. In this study, we develop a new 3D in vitro tissue model of microglia-containing retinal organoids by co-culturing ROs and hiPSC-derived macrophage precursor cells (MPCs). We optimized the parameters for successful integration of MPCs into retinal organoids. We show that while in the ROs, MPCs migrate to the equivalent of the outer plexiform layer where retinal microglia cells reside in healthy retinal tissue. While there, they develop a mature morphology characterized by small cell bodies and long branching processes which is only observed in vivo. During this maturation process these MPCs cycle through an activated phase followed by a stable mature microglial phase as seen by the down regulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines. Finally, we characterized mature ROs with integrated MPCs using RNAseq showing an enrichment of cell-type specific microglia markers. We propose that this co-culture system may be useful for understanding the pathogenesis of retinal diseases involving retinal microglia and for drug discovery directly in human tissue.

Persistence of vascular empty sleeves in choroidal neovascularization after VEGF therapy in both animal models and humans.

PURPOSE: Choroidal neovascularization (CNV) often recurs during anti-vascular endothelial growth factor (VEGF) therapy; however, little is known about the mechanism of vascular regrowth. Vascular regrowth along the empty sleeves of basement membranes was proposed as a mechanism for recurrence after the reversal of VEGF inhibition in tumors. This study investigated whether the proposed mechanism is involved in CNV during VEGF therapy. METHODS: We made two observations using a mice model, as well as patients with CNV. Laser-induced CNV mice were used to examine the vascular empty sleeves of the basement membrane and CNV with the immunohistochemistry of type IV collagen and CD31, respectively. A retrospective cohort study included 17 eyes from 17 patients with CNV treated with anti-VEGF treatment. Vascular regrowth during anti-VEGF treatment was assessed using optical coherence tomography angiography (OCTA). RESULTS: In the CNV mouse model, the CD31+ vascular endothelium area was decreased during anti-VEGF treatment compared with the IgG control (33516.7 ± 10864.7 vs. 10745.9 ± 5755.9 µm2, P < 0.05), whereas a significant difference was not observed in the area of type IV collagen+ vascular empty sleeve after the treatment compared with the control (29135.0 ± 7432.9 vs. 24592.0 ± 5935.3 µm2, P = 0.7). The proportions of CD31+ to type IV collagen+ areas were significantly decreased after the treatment (38.7 ± 7.4% vs. 17.1 ± 5.4%, P < 0.05). In the OCTA observations, the follow-up period in the retrospective cohort study was 58.2 ± 23.4 months. CNV regrowth was observed in 682 neovessels of the 17 eyes. In group 1, CNV regression and regrowth are in the same form (129 neovessels, 18.9%). In group 2, CNV regression and regrowth are in a different form (170 neovessels, 24.9%). In group 3, CNV regrowth is with a different form without the regression (383 neovessels, 56.2%). CONCLUSIONS: Parts of CNV regrowth may occur along the vascular empty sleeve, which remain after anti-VEGF treatment.

Animal model of subretinal fibrosis without active choroidal neovascularization.

Subretinal fibrosis can occur during neovascular age-related macular degeneration (nAMD) and consequently provokes progressing deterioration of AMD patient's vision. Intravitreal anti-vascular endothelial growth factor (VEGF) injections decrease choroidal neovascularization (CNV), however, subretinal fibrosis remains principally unaffected. So far, no successful treatment nor established animal model for subretinal fibrosis exists. In order to investigate the impact of anti-fibrotic compounds on solely fibrosis, we refined a time-dependent animal model of subretinal fibrosis without active choroidal neovascularization (CNV). To induce CNV-related fibrosis, wild-type (WT) mice underwent laser photocoagulation of the retina with rupture of Bruch's membrane. The lesions volume was assessed with optical coherence tomography (OCT). CNV (Isolectin B4) and fibrosis (type 1 collagen) were separately quantified with confocal microscopy of choroidal whole-mounts at every time point post laser induction (day 7-49). In addition, OCT, autofluorescence and fluorescence angiography were carried out at designated timepoints (day 7, 14, 21, 28, 35, 42, 49) to monitor CNV and fibrosis transformation over time. From 21 to 49 days post laser lesion leakage in the fluorescence angiography decreased. Correspondingly, Isolectin B4 decreased in lesions of choroidal flat mounts and type 1 collagen increased. Fibrosis markers, namely vimentin, fibronectin, alpha-smooth muscle actin (α-SMA) and type 1 collagen were detected at different timepoints of tissue repair in choroids and retinas post laser. These results prove that the late phase of the CNV-related fibrosis model enables screening of anti-fibrotic compounds to accelerate the therapeutic advancement for the prevention, reduction, or inhibition of subretinal fibrosis.

Real-time fundus reconstruction and intraocular mapping using an ophthalmic endoscope.

BACKGROUND: Robotic ophthalmic endoscope holders allow surgeons to execute dual-hand operations in eye surgery. To prevent needle-like endoscopes from invading the retina when moving, surgeons expect visual and real-time information about the relative special relationship between the endoscope and fundus. METHODS: This study develops a real-time fundus reconstruction method. First, using deep learning, the method estimates the distance between the fundus part corresponding to every pixel of the RGB endoscopic image and the endoscope. Then, by combining the estimated distance with the kinematics of a robotic holder, the point cloud representing the present fundus area is generated, and by which the size and position of the eyeball are estimated. RESULTS: This method shows a real-time frequency of 10 Hz, which is robust to eyeball movement. The error of fundus reconstruction is about 0.5 mm, and the error of eyeball estimation is about 1 mm. CONCLUSION: Using this fundus reconstruction method can map the position of the endoscope inside the eyeball when using a robotic endoscope holder in eye surgery. The overall accuracy level meets the ophthalmologists' accuracy requirements of ophthalmologists.

VOLUMETRIC THREE-DIMENSIONAL OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF RETINAL NEOVASCULARIZATION IN PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To evaluate structural and angiographic neovascularization in patients with proliferative diabetic retinopathy using volumetric three-dimensional optical coherence tomography angiography (OCTA). METHODS: This prospective, observational cross-sectional study included 29 eyes of 27 patients with proliferative diabetic retinopathy. The angiogenic structure, feeding vessel (epicenter), flow volume, and flow volume density of the neovasculatures were evaluated using three-dimensional OCTA imaging. The flow area and the flow area density were also measured using en face OCTA imaging. RESULTS: Sites of neovascularization were imaged successfully in 17 of the 29 eyes (58.6%). Three proposed types of neovascularization were identified on the basis of structural features seen on the three-dimensional OCTA images. Neovascularization of the adhesion type (9 of 17, 52.9%) adhered to the retinal vasculature. Those of the traction type (5 of 17, 29.4%) were partially separated from the retinal vascular plexus. Those of the mushroom type (3 of 17, 17.6%) were connected to the retinal vasculature by several epicenters. There was a significant difference between highly leaky (active) and faintly leaky (inactive) neovascularization for flow volume density, but not for flow area, flow volume, or flow area density ( P = 0.01, 0.9, 0.6, and 0.1, respectively). CONCLUSION: Volumetric three-dimensional OCTA revealed three types of neovascularization in proliferative diabetic retinopathy and may be useful for assessing neovascular activity and planning vitrectomies.

Longer Interscan Times in OCT Angiography Detect Slower Capillary Flow in Diabetic Retinopathy.

Purpose: To investigate the detection of slower retinal capillary blood flow using commercial OCT angiography (OCTA) with a longer interscan time in diabetic retinopathy (DR). Design: Observational, prospective, cross-sectional study. Participants: A total of 62 eyes from 39 subjects with diabetes mellitus and 10 eyes from 9 healthy subjects. Methods: Commercial spectral domain-OCT was used to obtain 3 × 3-mm fovea-centered OCTA images of all eyes with 3 different interscan times (4.3, 5.7, and 8.6 ms). For each interscan time, OCTA imaging was performed 5 consecutive times, and a ×5 averaged image was obtained. Capillary flow density and visualization of retinal capillaries in the superficial and deep capillary plexuses (SCPs and DCPs, respectively) were compared between the 3 averaged images from the 3 different interscan times. Main Outcome Measures: Capillary flow density and visualization of foveal capillaries in 3 images with different interscan times. Results: Forty-five eyes of 34 patients were analyzed. There was no significant difference in the flow density of the SCP and DCP between the 3 images with different interscan times in all the DR stages. Some capillaries including microaneurysms that could not be observed at 4.3 ms could be observed at 5.7 or 8.6 ms. There were significantly more capillaries with difference points between the 3 images in the group with DR than in the group without DR (P < 0.01). The morphology of some microaneurysms also changed with longer interscan times. Conclusions: OCTA with longer interscan times revealed slower flow points in capillaries and more accurate visualization and morphology of microaneurysms in DR.

Identifying Hyperreflective Foci in Diabetic Retinopathy via VEGF-Induced Local Self-Renewal of CX3CR1+ Vitreous Resident Macrophages.

Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been examined in diabetic retinopathy (DR). A prospective observational clinical study with 162 consecutive eyes using OCT imaging showed significantly increased HRF at the VRI during DR progression (P < 0.01), which was reversed by anti-vascular endothelial growth factor (VEGF) therapy. F4/80+ macrophages increased significantly at the VRI in Kimba (vegfa+/+) or Akimba (Akita × Kimba) mice (both P < 0.01), but not in diabetic Akita (Ins2+/-) mice, indicating macrophage activation was modulated by elevated VEGF rather than the diabetic milieu. Macrophage depletion significantly reduced HRF at the VRI (P < 0.01). Furthermore, BrdU administration in Ccr2rfp/+Cx3cr1gfp/+vegfa+/- mice identified a significant contribution of M2-like tissue-resident macrophages (TRMs) at the VRI. Ki-67+ and CD11b+ cells were observed in preretinal tissues of DR patients, while exposure of vitreal macrophages to vitreous derived from PDR patients induced a significant proliferation response in vitro (P < 0.01). Taken together, the evidence suggests that VEGF drives a local proliferation of vitreous resident macrophages (VRMs) at the VRI during DR. This phenomenon helps to explain the derivation and disease-relevance of the HRF lesions observed through OCT imaging in patients.

Hyperreflective Membrane at the Vitreoretinal Interface in Diabetic Macular Edema: A Finding in Ultra-High-Resolution Optical Coherence Tomography.

Purpose: Detecting subtle vitreoretinal interface (VRI) findings, such as a posterior hyaloid membrane, is difficult with conventional retinal imaging. We compared ultra-high-resolution spectral domain optical coherence tomography (UHR-SD-OCT) with standard-resolution OCT (SD-OCT) for the imaging of VRI abnormalities in diabetic retinopathy (DR). Methods: This prospective cross-sectional study included 113 consecutive patients (91 patients with diabetes and 22 healthy controls). The VRI was evaluated, and the results were compared between the conventional SD-OCT and UHR-SD-OCT images. VRI findings were also investigated before and after internal limiting membrane peeling during vitrectomy for proliferative DR. Results: A total of 159 eyes (87.4%) of 91 patients with diabetes were analyzed. UHR-SD-OCT could detect a hyperreflective layer at the VRI, in which en face OCT showed a membrane-like structure, termed the hyperreflective membrane (HRMe). The preoperative HRMe could not be detected in all patients with proliferative DR who underwent internal limiting membrane peeling during vitrectomy. Although the HRMe did not correlate with the DR stage, eyes with diabetic macular edema (DME) (64.5%) showed a significant HRMe with UHR-SD-OCT more frequently than those without DME (35.8%) (P = 0.005). Conclusions: UHR-SD-OCT can detect the HRMe at the VRI in DR eyes, particularly in eyes with DME. The HRMe may present a thickened posterior hyaloid membrane that contributes to DME development. Translational Relevance: UHR-SD-OCT detects slight changes in the VRI in DR eyes. In the future, it may help to elucidate the mechanism of DME formation.

Morphology and fluorescein leakage in diabetic retinal microaneurysms: a study using multiple en face OCT angiography image averaging.

PURPOSE: To investigate the relevance of microaneurysm morphology in optical coherence tomography angiography (OCTA) image averaging and fluorescein leakage in diabetic retinopathy (DR). METHODS: In 38 consecutive patients with DR, ten consecutive 3- × 3-mm fovea-centered OCTA (HS100, Canon Inc., Tokyo, Japan) and fluorescein angiography (FA) were performed, and averaged OCTA images were created based on the 10 images. After detecting all microaneurysms in FA images, the morphology was classified into four types (focal bulge, saccular/pedunculated, fusiform, and mixed) using averaged OCTA images. The correlation between microaneurysm leakage in FA, retinopathy stage, and microaneurysm morphology was estimated. RESULTS: Thirty-eight eyes (50.0%) of the 33 patients were available for analysis, and 370 (63.5%) of the 583 FA-detected microaneurysms were morphologically classifiable (focal bulge, 46; saccular/pedunculated, 143; fusiform, 29; and mixed, 152) in OCTA. There was a significant correlation between stage and percentage of microaneurysm morphology and between morphology and the presence of leakage (P < 0.0001 and P < 0.01, respectively). The proportion of focal bulges decreased with stage progression, while the other three types increased with stage progression. The percentage of FA leakage for focal bulge, saccular/pedunculated, fusiform, and mixed was 41.3%, 66.4%, 82.8%, and 66.4%, respectively, and the fusiform type showed significant FA leakage. CONCLUSION: Microaneurysm morphology is correlated with the DR stage and FA leakage. Microaneurysm morphology recognition using OCTA image averaging may be useful for the clinical evaluation of DR.

Circulating inflammatory monocytes oppose microglia and contribute to cone cell death in retinitis pigmentosa.

Retinitis pigmentosa (RP) is an intractable inherited disease that primarily affects the rods through gene mutations followed by secondary cone degeneration. This cone-related dysfunction can lead to impairment of daily life activities, and ultimately blindness in patients with RP. Paradoxically, microglial neuroinflammation contributes to both protection against and progression of RP, but it is unclear which population(s) - tissue-resident microglia and/or peripheral monocyte-derived macrophages (mφ) - are implicated in the progression of the disease. Here we show that circulating blood inflammatory monocytes (IMo) are key effector cells that mediate cone cell death in RP. Attenuation of IMo and peripherally engrafted mφ by Ccl2 deficiency or immune modulation via intravenous nano-particle treatment suppressed cone cell death in rd10 mice, an animal model of RP. In contrast, the depletion of resident microglia by a colony-stimulating factor 1 receptor inhibitor exacerbated cone cell death in the same model. In human patients with RP, IMo was increased and correlated with disease progression. These results suggest that peripheral IMo is a potential target to delay cone cell death and prevent blindness in RP.