A Case of an Elderly Woman Who Developed Corneal Perforation in the Clinical Course of Myeloperoxidase Positive Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is a systemic vasculitis characterized by ANCA positivity and categorized into three main types: microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatous with polyangiitis. Although AAV leads to systemic organ injury, such as of the lungs, kidneys, nerves, and skin, patients with AAV sometimes develop ocular lesions. Here, we report the case of an elderly woman who had been treated for AAV for seven years. She developed scleritis and relapsed twice, with elevation of serum disease markers such as ANCA titer and C-reactive protein. After the decline of these markers due to treatment with additional medication, her scleritis relapsed again and caused a corneal ulcer, which resulted in perforation without obvious marker elevation. She did not present with any symptoms of organ injury, except for ocular lesions. She was treated with surgery, followed by methylprednisolone and rituximab therapy. Subsequently, her ocular lesions and symptoms improved, and she did not relapse. AAV can cause various ocular manifestations. Although C-reactive protein and ANCA titers are useful markers of disease activity and the relapse of AAV complications, including ocular lesions, these markers do not always increase at the time of worsening ocular lesions. Therefore, it is important for clinicians treating patients with AAV to pay careful attention to serum data and physical findings, including the eyes.

Role of Adrenomedullin 2/Intermedin in the Pathogenesis of Neovascular Age-Related Macular Degeneration.

Adrenomedullin 2 (AM2; also known as intermedin) is a member of the adrenomedullin (AM) peptide family. Similarly to AM, AM2 partakes in a variety of physiological activities. AM2 has been reported to exert protective effects on various organ disorders; however, its significance in the eye is unknown. We investigated the role of AM2 in ocular diseases. The receptor system of AM2 was expressed more abundantly in the choroid than in the retina. In an oxygen-induced retinopathy model, physiological and pathologic retinal angiogenesis did not differ between AM2-knockout (AM2-/-) and wild-type mice. In contrast, in laser-induced choroidal neovascularization, a model of neovascular age-related macular degeneration, AM2-/- mice had enlarged and leakier choroidal neovascularization lesions, with exacerbated subretinal fibrosis and macrophage infiltration. Contrary to this, exogenous administration of AM2 ameliorated the laser-induced choroidal neovascularization-associated pathology and suppressed gene expression associated with inflammation, fibrosis, and oxidative stress, including that of VEGF-A, VEGFR-2, CD68, CTGF, and p22-phox. The stimulation of human adult retinal pigment epithelial (ARPE) cell line 19 cells with TGF-ß2 and TNF-α induced epithelial-to-mesenchymal transition (EMT), whereas AM2 expression was also elevated. The induction of EMT was suppressed when the ARPE-19 cells were pretreated with AM2. A transcriptome analysis identified 15 genes, including mesenchyme homeobox 2 (Meox2), whose expression was significantly altered in the AM2-treated group compared with that in the control group. The expression of Meox2, a transcription factor that inhibits inflammation and fibrosis, was enhanced by AM2 treatment and attenuated by endogenous AM2 knockout in the early phase after laser irradiation. The AM2 treatment of endothelial cells inhibited endothelial to mesenchymal transition and NF-κB activation; however, this effect tended to be canceled following Meox2 gene knockdown. These results indicate that AM2 suppresses the neovascular age-related macular degeneration-related pathologies partially via the upregulation of Meox2. Thus, AM2 may be a promising therapeutic target for ocular vascular diseases.

Impact of local COVID-19 alert levels on rhegmatogenous retinal detachment.

PURPOSE: To investigate the impact of the local alert levels regarding coronavirus disease 2019 (COVID-19) on the clinical patterns of rhegmatogenous retinal detachment (RRD) in Japan. STUDY DESIGN: Retrospective, single-center, consecutive case series. METHODS: We compared two groups of RRD patients, a COVID-19 pandemic group and a control group. Based on the local alert levels in Nagano, five periods during the COVID-19 pandemic were further analyzed: epidemic 1 (state of emergency), inter-epidemic 1, epidemic 2 (second epidemic duration), inter-epidemic 2, and epidemic 3 (third epidemic duration). Patients' characteristics, including symptoms' duration before visiting our hospital, macula status, and retinal detachment (RD) recurrence rate in each period, were compared with those in a control group. RESULTS: There were 78 patients in the pandemic group and 208 in the control group. The pandemic group had a longer duration of symptoms than the control group (12.0 ± 13.5 days vs. 8.9 ± 14.7 days, P = 0.0045). During the epidemic 1 period, patients had a higher rate of macula-off RRD (71.4% vs. 48.6%) and RD recurrence (28.6% vs. 4.8%) than the control group. This period also demonstrated the highest rates compared to all other periods in the pandemic group. CONCLUSION: During the COVID-19 pandemic, RRD patients significantly delayed visiting a surgical facility. They showed a higher rate of macula-off and recurrence compared to the control group during the state of emergency than during other periods of the COVID-19 pandemic, although the difference was not statistically significant due to the small sample size.

UVA induces retinal photoreceptor cell death via receptor interacting protein 3 kinase mediated necroptosis.

Ultraviolet light A (UVA) is the only UV light that reaches the retina and can cause indirect damage to DNA via absorption of photons by non-DNA chromophores. Previous studies demonstrate that UVA generates reactive oxygen species (ROS) and leads to programmed cell death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor interacting protein 1 and 3 (RIPK1 and RIPK3) kinases, key signaling molecules of PCD, in UVA-induced photoreceptor injury using in vitro and ex vivo models. UVA irradiation activated RIPK3 but not RIPK1 and mediated necroptosis through MLKL that lie downstream of RIPK3 and induced apoptosis through increased oxidative stress. Moreover, RIPK3 but not RIPK1 inhibition suppresses UVA-induced cell death along with the downregulation of MLKL and attenuates the levels of oxidative stress and DNA fragmentation. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced necroptosis cell death in photoreceptors and highlight RIPK3 potential as a neuroprotective target.

Receptor interacting protein 3 kinase, not 1 kinase, through MLKL-mediated necroptosis is involved in UVA-induced corneal endothelium cell death.

Ultraviolet (UV) is one of the most energetic radiations in the solar spectrum that can result in various tissue injury disorders. Previous studies demonstrated that UVA, which represents 95% of incident photovoltaic radiation, induces corneal endothelial cells (CECs) death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor-interacting protein 3 kinase (RIPK3), a key signaling molecule of PCD, in UVA-induced injury using a short-term corneal endothelium (CE) culture model. UVA irradiation activated RIPK3 and mediated necroptosis both in mouse CE and primary human CECs (pHCECs). UVA irradiation was associated with upregulation of key necroptotic molecules (DAI, TRIF, and MLKL) that lie downstream of RIPK3. Moreover, RIPK3 inhibition or silencing in primary corneal endothelial cells suppresses UVA-induced cell death, along with downregulation of MLKL in pHCECs. In addition, genetic inhibition or knockout of RIPK3 in mice (RIPK3K51A and RIPK3-/- mice) similarly attenuates cell death and the levels of necroptosis in ex vivo UVA irradiation experiments. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced cell death in CE and indicate its potential as a future protective target.

Adrenomedullin-Receptor Activity-Modifying Protein 2 System Ameliorates Subretinal Fibrosis by Suppressing Epithelial-Mesenchymal Transition in Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti-vascular endothelial growth factor drugs used to treat AMD carry the risk of inducing subretinal fibrosis. We investigated the use of adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein 2, RAMP2, which regulate vascular homeostasis and suppress fibrosis. The therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis, and macrophage invasion were all enhanced in both AM and RAMP2 knockout mice compared with those in wild-type mice. These pathologic changes were suppressed by intravitreal injection of AM. Comprehensive gene expression analysis of the choroid after LI-CNV with or without AM administration revealed that fibrosis-related molecules, including Tgfb, Cxcr4, Ccn2, and Thbs1, were all down-regulated by AM. In retinal pigment epithelial cells, co-administration of transforming growth factor-ß and tumor necrosis factor-α induced epithelial-mesenchymal transition, which was also prevented by AM. Finally, transforming growth factor-ß and C-X-C chemokine receptor type 4 (CXCR4) inhibitors eliminated the difference in subretinal fibrosis between RAMP2 knockout and wild-type mice. These findings suggest the AM-RAMP2 system suppresses subretinal fibrosis in LI-CNV by suppressing epithelial-mesenchymal transition.

Neuroprotective effects and mechanisms of action of nicotinamide mononucleotide (NMN) in a photoreceptor degenerative model of retinal detachment.

Currently, no pharmacotherapy has been proven effective in treating photoreceptor degeneration in patients. Discovering readily available and safe neuroprotectants is therefore highly sought after. Here, we investigated nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD+), in a retinal detachment (RD) induced photoreceptor degeneration. NMN administration after RD resulted in a significant reduction of TUNEL+ photoreceptors, CD11b+ macrophages, and GFAP labeled glial activation; a normalization of protein carbonyl content (PCC), and a preservation of the outer nuclear layer (ONL) thickness. NMN administration significantly increased NAD+ levels, SIRT1 protein expression, and heme oxygenase-1 (HO-1) expression. Delayed NMN administration still exerted protective effects after RD. Mechanistic in vitro studies using 661W cells revealed a SIRT1/HO-1 signaling as a downstream effector of NMN-mediated protection under oxidative stress and LPS stimulation. In conclusion, NMN administration exerts neuroprotective effects on photoreceptors after RD and oxidative injury, suggesting a therapeutic avenue to treating photoreceptor degeneration.

Prediction of post-treatment retinal sensitivity by baseline retinal perfusion density measurements in eyes with branch retinal vein occlusion.

In this study, we investigated the longitudinal correlation between macular sensitivity and perfusion density (PD) in retinas affected by branch retinal vein occlusion. Retinal sensitivity was measured using microperimetry and PD was measured by optical coherence tomography angiography. We also investigated the possibility that the PD, 1 month after anti-vascular endothelial growth factor (VEGF) treatment, is a predictor of retinal sensitivity after 1 year of successful macular oedema management with anti-VEGF. The correlation between measurements of retinal sensitivity and PD at baseline (1 M) and at 6 and 12 months were investigated. There was a significant positive correlation between retinal sensitivity and PD at all time points (baseline (1 M), r = 0.67, P < 0.0001; 6 months, r = 0.59, P < 0.0001; 12 months, r = 0.62, P < 0.0001) and between the PD at 1 month and retinal sensitivity at 12 months (r = 0.63, P < 0.0001). Unlike in areas that showed a mild to moderate decline in PD, retinal sensitivity in areas where the decrease in PD was severe at baseline did not show significant improvement with treatment over time. These findings suggest that the PD value measured using optical coherence tomography angiography at or soon after the baseline can predict retinal sensitivity after 1 year of anti-VEGF treatment.

Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells.

Lysosome-associated membrane protein-2 (LAMP2), is a highly glycosylated lysosomal membrane protein involved in chaperone mediated autophagy. Mutations of LAMP2 cause the classic triad of myopathy, cardiomyopathy and encephalopathy of Danon disease (DD). Additionally, retinopathy has also been observed in young DD patients, leading to vision loss. Emerging evidence show LAMP2-deficiency to be involved in oxidative stress (ROS) but the mechanism remains obscure. In the present study, we found that tert-butyl hydroperoxide or antimycin A induced more cell death in LAMP2 knockdown (LAMP2-KD) than in control ARPE-19 cells. Mechanistically, LAMP2-KD reduced the concentration of cytosolic cysteine, resulting in low glutathione (GSH), inferior antioxidant capability and mitochondrial lipid peroxidation. ROS induced RPE cell death through ferroptosis. Inhibition of glutathione peroxidase 4 (GPx4) increased lethality in LAMP2-KD cells compared to controls. Cysteine and glutamine supplementation restored GSH and prevented ROS-induced cell death of LAMP2-KD RPE cells.

Development of a Novel Model of Central Retinal Vascular Occlusion and the Therapeutic Potential of the Adrenomedullin-Receptor Activity-Modifying Protein 2 System.

Central retinal vein occlusion (CRVO) is an intractable disease that causes visual acuity loss with retinal ischemia, hemorrhage, and edema. In this study, we developed an experimental CRVO model in mice and evaluated the therapeutic potential of the pleiotropic peptide adrenomedullin (ADM) and its receptor activity-modifying protein 2 (RAMP2). The CRVO model, which had phenotypes resembling those seen in the clinic, was produced by combining i.p. injection of Rose bengal, a photoactivator dye enhancing thrombus formation, with laser photocoagulation. Retinal vascular area, analyzed using fluorescein angiography and fluorescein isothiocyanate-perfused retinal flat mounts, was decreased after induction of CRVO but gradually recovered from day 1 to 7. Measurements of retinal thickness using optical coherence tomography and histology revealed prominent edema early after CRVO, followed by gradual atrophy. Reperfusion after CRVO was diminished in Adm and Ramp2 knockout (KO) mice but was increased by exogenous ADM administration. CRVO also increased expression of a coagulation factor, oxidative stress markers, and a leukocyte adhesion molecule in both wild-type and Adm KO mice, and the effect was more pronounced in Adm KO mice. Using retinal capillary endothelial cells, ADM was found to directly suppress retinal endothelial injury. The retinoprotective effects of the Adm-Ramp2 system make it a novel therapeutic target for the treatment of CRVO.

Effect of Leaking Foveal Microaneurysms on the Treatment of Center-Involving Diabetic Macular Edema: A Pilot Study.

PURPOSE: Evaluate the effect of foveal leaking microaneurysms (MAs) on the required number of intravitreal ranibiz-umab (IVR) injections in the treatment of center-involving diabetic macular edema (DME) when treated with focal/grid laser. DESIGN: A pilot study of prospective, nonrandomized, multicenter clinical trial. METHODS: This study enrolled 21 eyes with DME for which pro re nata IVR injections were combined with short-pulse focal/grid laser. At 12 months, best-corrected visual acuity (BCVA), central subfield macular thickness (CMT), and the required number of IVRs to maintain CMT < 300 µm were compared between eyes with or without foveal leaking MAs, termed the MA(+) and MA(-) groups, respectively. RESULTS: Significant CMT improvements (p < 0.0001) and increased BCVA of 4.0 ± 8.5 letters were observed at 12 months. The MA(-) group required significantly fewer IVRs than did the MA(+) group (mean: 4.9 ± 3.0 vs. 8.6 ± 3.0; p = 0.0306). In the latter 6 months of the 1-year follow-up, 50% (4/8) of MA(-) eyes did not require any IVR administration to sustain CMT < 300 µm. CONCLUSIONS: A combination therapy of short-pulse focal/grid laser and reduced IVR injections appeared noninferior to previous reports of IVR monotherapy. Further large-scale investigations are warranted.

Complete regression of branching vascular network in polypoidal choroidal vasculopathy by ranibizumab and photodynamic therapy, two case reports.

BACKGROUND: Polypoidal choroidal vasculopathy (PCV) consists of polyps that potentially cause massive subretinal hemorrhage and their branching vascular network (BVN) of feeder vessels. Although conventional indocyanine green angiography (IA) has shown anti-vascular endothelial growth factor (VEGF) agents and/or photodynamic therapy (PDT) to successfully induce polyp closure, the BVN appears resistant to these therapies and serves as the origin of recurrent active polyps. Recently introduced optical coherence tomography angiography (OCT-A) enables more frequent angiographic evaluation of polyps and the BVN than does conventional IA since it does not require intravenous fluorescent dye injection and is thus considered non-invasive. CASE PRESENTATION: Case 1. A 70-year-old male with PCV in his left eye suffered from vision deterioration (20/40) due to persistent subretinal fluid despite 42 intravitreal injections of ranibizumab (IVRs) over 5 years and 7 months. PDT was performed as an adjunct therapy 3 days after the 43rd IVR. IA at 3 months after PDT showed successful polyp closure but persisting BVN. However, more frequent evaluation with OCT-A starting at 1 week after PDT demonstrated complete regression of both the BVN and polyp. OCT-A at every subsequent outpatient visit depicted gradual re-perfusion of the BVN and the restoration of most of its original network at 3 months, which was compatible with IA findings. Neither OCTA nor IA revealed polyp recurrence at 3 months. Case 2. A 65-year-old female suffering from left vision deterioration due to PCV underwent 5 intravitreal injections of aflibercept. Since her subretinal fluid persisted, the treatment was switched to a combination of IVR and PDT. OCT-A revealed marked regression of the BVN and polyp at 2 weeks, but the BVN had regained its original shape at 2 months without any sign of polyp recurrence. CONCLUSIONS: Differently from previous observations obtained by IA alone, more frequent non-invasive OCT-A examination revealed complete but transient regression of the BVN just after combination therapy with IVR and PDT.

Extended field imaging using swept-source optical coherence tomography angiography in retinal vein occlusion.

PURPOSE: To evaluate the degree of ischemia in eyes with retinal vein occlusion (RVO) using swept-source optical coherence tomography angiography (SS-OCTA) with the extended field imaging (EFI) technique, which extends the area encompassed by SS-OCTA by scanning through trial frames fitted with a +20-diopter lens. STUDY DESIGN: Retrospective observational study. METHODS: Twenty-three consecutive eyes of 22 patients with RVO underwent 12 × 12 mm SS-OCTA imaging both with and without EFI for determination of extension rate. Two graders blinded to the clinical data evaluated the degree of retinal ischemia in paired EFI-SS-OCTA and fluorescein angiography (FA) images, and the concordance rates between the grades were statistically examined. RESULTS: One EFI-SS-OCTA image was not successfully obtained due to motion artifacts caused by the patient's poor central vision, while SS-OCTA images without EFI were captured in all 23 eyes. The average extension rate of EFI-SS-OCTA over SS-OCTA was 1.39 ± 0.06 and the average scanning area was enlarged by 76.4%. Two graders evaluated the degree of retinal ischemia by measuring nonperfusion areas as the sum of disc areas/diameters. Although their assessments of the EFI-SS-OCTA images were in complete agreement (Cohen's Unweighted Kappa coefficient = 1.00), concordance using FA images was only moderate (Cohen's Unweighted Kappa coefficient = 0.60). CONCLUSION: EFI-SS-OCTA noninvasively produces wider field images of retinal vasculature with one capture and provides resolution sufficient to accurately evaluate retinal capillary nonperfusion in RVO.

CHANGES IN PLASMA VASCULAR ENDOTHELIAL GROWTH FACTOR LEVEL AFTER INTRAVITREAL INJECTION OF BEVACIZUMAB, AFLIBERCEPT, OR RANIBIZUMAB FOR DIABETIC MACULAR EDEMA.

PURPOSE: The aim of this study was to investigate the changes in plasma vascular endothelial growth factor (VEGF) level depending on the severity of diabetic retinopathy (DR) or diabetic macular edema (DME) and after intravitreal injection of bevacizumab, aflibercept, or ranibizumab for treatment of DME. METHODS: Plasma VEGF level was evaluated in 72 patients with DR and changes were measured in 42 patients with DME receiving intravitreal injections of bevacizumab, aflibercept, or ranibizumab at the initial injection. RESULTS: There were no correlations between plasma VEGF level and the severity of DME or DR. Baseline plasma VEGF level (51.9 pg/mL) was significantly reduced using bevacizumab to 11.9 pg/mL after 1 week and 24.1 pg/mL after 4 weeks (P = 0.0130 and 0.0201, respectively). In aflibercept-treated eyes, plasma VEGF decreased from 52.2 pg/mL to 7.8 pg/mL and 12.6 pg/mL, respectively, at the same time points (both P < 0.001). No such reductions were observed in patients receiving ranibizumab. CONCLUSION: Baseline plasma VEGF level showed no correlations with DR or DME severity, whereas intravitreal injection of bevacizumab or aflibercept significantly reduced plasma VEGF for up to 4 weeks and ranibizumab produced no such effects. Changes in plasma VEGF level seemed not to be critical in progression or treatment of DME and DR.

Adrenomedullin Suppresses Vascular Endothelial Growth Factor-Induced Vascular Hyperpermeability and Inflammation in Retinopathy.

Diabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.

Marked biochemical difference in amyloid proportion between intra- and extraocular tissues in a liver-transplanted patient with hereditary ATTR amyloidosis.

In order to elucidate the pathomechanism of ocular amyloid formation in a liver-transplanted patient with hereditary ATTR amyloidosis, we investigated detailed biochemical features of ocular amyloid. The patient was a 49-year-old woman with V30M transthyretin (TTR) variant (p.TTRV50M), who underwent ophthalmectomy due to corneal rupture 10 years after liver transplantation (LT). The amyloid was selectively isolated from several portions in intra- and extraocular tissues using a laser microdissection (LMD) system and analyzed by liquid chromatography-tandem mass spectrometry to determine the composition percentage of wild-type and variant TTR in the isolated amyloid. Biochemical analysis revealed that the amyloid consisted mainly of variant TTR in intraocular tissues with a percentage > 80%. On the contrary in the extraocular muscles, wild-type TTR was the main component of the amyloid with a percentage of ∼70%. Our data indicate that intraocular amyloid formation strongly depends on locally synthesized variant TTR and the contribution of wild-type TTR to amyloid formation is quite limited.

Effect of leaking perifoveal microaneurysms on resolution of diabetic macular edema treated by combination therapy using anti-vascular endothelial growth factor and short pulse focal/grid laser photocoagulation.

PURPOSE: The effect of combination therapy using intravitreal ranibizumab (IVR) injections and short pulse focal/grid laser photocoagulation was evaluated for the treatment of diabetic macular edema (DME). METHODS: The current investigation was a preliminary single-arm, open-label, prospective clinical study conducted on 21 eyes at 4 sites in Japan. Treatment protocol consisted of two phases. The induction IVR phase included two monthly IVRs followed by PRN IVR phase in which additional IVR was administered if the central macular thickness (CMT) exceeded 300 µm. One week after each IVR in both phases, short pulse focal/grid laser was delivered to treat residual leakage outside of the fovea (>500 µm) and reduce edema fluid influx. At the 6-month endpoint, the effects of treatment were examined in terms of best corrected visual acuity (BCVA), CMT, and required number of IVR injections in eyes with or without perifoveal leaking microaneurysms (MAs). RESULTS: In eyes with initial BCVA ≤70 letters, mean BCVA was significantly ameliorated by 7.0 ± 7.4 letters (P = 0.0324) and mean CMT improved significantly by 174.8 ± 105.0 µm (P = 0.0005). Both BCVA improvement (P = 0.8693) and CMT reduction (P = 0.9336) were comparable between MA(-) and MA(+) groups. The MA(-) group required significantly fewer PRN-IVR injections than did the MA(+) group over the 6-month study period (mean 3.4 ± 1.6 vs. 5.3 ± 0.9, median 3.0 vs. 5.5; P = 0.0229). CONCLUSIONS: Short pulse focal/grid laser photocoagulation could reduce the number of IVR injections required to resolve macular edema and increase BCVA in a possible mechanism of reduced influx of edema fluid into the foveal area in eyes without apparent perifoveal microaneurysms.