Retinal arterial occlusive vasculitis after multiple intravitreal brolucizumab injections for diabetic macular edema.

Purpose: To describe a case of unilateral retinal arterial occlusive vasculitis after multiple intravitreal brolucizumab (IVBr) treatments for diabetic macular edema (DME). Observations: A 68-year-old Japanese woman who had a 3-year history of insulin-dependent diabetes mellitus presented with decreased vision in the right eye (oculus dexter, OD). After two consecutive IVBr (3 mg) treatments for DME, spaced 6 weeks apart, her best corrected visual acuity improved from 20/32 to 20/28 OD, as central macular thickness (CMT) decreased from 368 µm to 253 µm on optical coherence tomography (OCT). Immediately after the 3rd IVBr, the right intraocular pressure (IOP) increased. One week later, iritis (aqueous flares: 65.0 photon count [PC]/ms) was observed, followed by localized vasculitis 2 weeks later. One month after the 3rd IVBr, extensive vasculitis and vasculitis occluding retinal arterioles were identified. Based on the history of IVBr use and clinical findings, intraocular inflammation (IOI) and subsequent retinal arterial occlusive vasculitis due to IVBr was diagnosed. Topical steroid administration (i.e., eye drops and subtenon injection) resulted in improvement of IOI after 3 months. She subsequently underwent two intravitreal aflibercept injections for DME and panretinal photocoagulation (PRP) to prevent the development of proliferative changes due to diabetic retinopathy. One year after the diagnosis of retinal arterial occlusive vasculitis, the patient had slight loss of vision (20/50) compared to baseline, due to the progression of cataracts, and OCT angiography (OCTA) showed extensive non-perfusion area on the temporal side. However, other examination findings (IOP: 16 mmHg, aqueous flares: 30.5 PC/ms, CMT: 283 µm) were stable. Conclusions and importance: Diagnosis and treatment at a relatively early stage after the onset of IOI prevented severe visual impairment in this case. Topical betamethasone eye drops reduced anterior chamber inflammation associated with IVBr; however, vascular sheathing worsened when topical drops alone was used. Occlusive retinal vasculitis, diagnosed with fluorescein angiography (FA) and OCTA, appeared to stabilize when subtenon triamcinolone injection was added to topical steroid administration. Because the central macula was not involved, severe vision loss was prevented. It is unknown if topical steroid administration would be adequate to prevent worsening of occlusive vasculitis in other cases. Although not used in this case, oral prednisone is one treatment option that may prevent severe vision loss. However, it requires monitoring of side effects, such as elevated blood glucose levels. PRP is also an option in cases where progression of proliferative changes is a concern, as was done in this case. With these considerations in mind, it is important to diagnose brolucizumab-associated IOI and subsequent retinal arterial occlusive vasculitis in DME patients early and initiate treatment to prevent severe visual impairment. Diagnosing new IOI and subsequent retinal arterial occlusive vasculitis is more difficult in DME than in neovascular age-related macular degeneration because of the inflammatory component often associated vascular occlusions. Therefore, early IOI diagnosis and follow-up using various instruments such as laser flare cell meter, wide-field color imaging, OCT/OCTA, and FA, in addition to usual comprehensive ophthalmologic examinations, is crucial.

Outcomes of a 2-year treat-and-extend regimen with aflibercept for diabetic macular edema.

This prospective, open-label, single-arm, non-randomized clinical trial, assessed the efficacy of a 2-year treat-and-extend (T&E) regimen involving intravitreal aflibercept injection (IAI), with the longest treatment interval set to 16 weeks, and adjunct focal/grid laser in diabetic macula edema (DME) patients. We examined 40 eyes (40 adults) with fovea-involving DME from 8 Japanese centers between April 2015 and February 2017. Participants received IAI with an induction period featuring monthly injections and a subsequent T&E period featuring 8-16-week injection interval, adjusted based on optical coherence tomography findings. The primary endpoints were mean changes in the best-corrected visual acuity (BCVA) and central subfield macular thickness (CST) from baseline. Thirty patients (75%) completed the 2-year follow-up. The mean BCVA and CST changed from 60.5 ± 15.6 letters and 499.2 ± 105.6 µm at baseline to 66.6 ± 17.1 letters (P = 0.217) and 315.2 ± 79.0 µm (P < 0.001), respectively, after 2 years. The treatment interval was extended to 12 and 16 weeks in 6.7% and 66.7% of patients, respectively, at the end of 2 years. The T&E aflibercept regimen with the longest treatment interval set to 16 weeks, with adjunct focal/grid laser may be a rational 2-year treatment strategy for DME.

Treat-and-extend therapy with aflibercept for diabetic macular edema: a prospective clinical trial.

PURPOSE: To investigate the efficacy and safety of a treat-and-extend (T&E) regimen using aflibercept (Eylea) for diabetic macular edema (DME). STUDY DESIGN: Prospective, open-label, multicenter, single-arm, nonblinded clinical study. METHODS: Forty eyes of 40 patients with DME received a T&E regimen of intravitreal aflibercept injection (IAI) with the longest treatment interval set to 16 weeks and adjunct focal/grid laser for 1 year. An intent-to-treat analysis was performed using the same last-observation-carried-forward method. A per-protocol analysis was also performed for patients who completed a 1-year T&E regimen. The primary endpoints were mean changes in best-corrected visual acuity (BCVA) and central subfield macular thickness (CST) from baseline. Secondary endpoints included IAI-interval extension and resultant IAI numbers and the association between an early response to IAI and final BCVA gain at 1 year. RESULTS: Thirty-one patients (77.5%) completed the 1-year aflibercept T&E regimen. In these per-protocol participants, the mean CST improvement/reduction was 187.3 ± 145.0 µm (P < .001), but the mean BCVA gain was limited to 4.3 ± 12.2 letters (P = .782). Subanalysis revealed that eyes that gained ≥ 4 letters (median at week 12) after the initial 3 consecutive IAIs (induction phase) achieved greater vision improvement (13.8 ± 9.5 letters) than did the residual eyes (- 4.3 ± 9.2 letters) at 1 year (P < .001). Treatment intervals were extended to 12 and 16 weeks in 16.1% (5/31) and 45.2% (14/31) of the patients, respectively. The mean IAI number was 7.0 ± 1.1. CONCLUSIONS: The results of this study suggest that although the BCVA improvement might be somewhat less than that of frequent treatment, a T&E aflibercept regimen with the longest treatment interval set to 16 weeks is a realizable rational strategy for DME treatment over 1 year.

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.

Vitreoretinal Interface Slab in OCT Angiography for Detecting Diabetic Retinal Neovascularization.

PURPOSE: To compare neovascularization identified in proliferative diabetic retinopathy (PDR) eyes by widefield swept-source (SS) OCT angiography (OCTA) using vitreoretinal interface (VRI) slab images, composed by automated and manual segmentation, with that identified by fluorescein angiography (FA). DESIGN: Retrospective study. PARTICIPANTS: Forty-two eyes of 30 treatment-naïve PDR patients who visited the outpatient clinic of the Department of Ophthalmology, Shinshu University, from June 2018 through October 2019. METHODS: All patients underwent comprehensive ophthalmologic examinations, including SS-OCTA and FA. MAIN OUTCOME MEASURES: Neovascularization detected by en face SS-OCTA 15 × 15-mm VRI slab images and by FA in the same 15 × 15-mm areas were compared in terms of number and structure. RESULTS: Among 100 neovascularizations detected by FA, 73 also were visualized as neovascularization in SS-OCTA VRI slab images using automated segmentation. The sensitivity of VRI slab images for detecting neovascularization was 73%. Among the remaining 27 neovascularizations detected only by FA, but not by VRI slab, 15 were intraretinal microvascular abnormalities with fluorescence leakage, 1 was a diabetic papillopathy, and 11 were flat neovascularizations on the internal limiting membrane surface that were missed because of segmentation error. Conversely, among the 98 neovascularizations detected on VRI slab images, 25 were not detected as neovascularizations by FA. They included 9 small neovascularizations that exhibited too little leakage on FA and 16 false-positive results that were the result of segmentation errors. After reconstruction of SS-OCTA VRI slab images by means of manual segmentation, the sensitivity of VRI slab images for detecting neovascularizations increased to 84%. CONCLUSIONS: The efficacy of SS-OCTA VRI slab images for detecting neovascularizations in PDR was comparable with that of FA. Swept-source OCTA VRI slab images may be better than FA for identifying intraretinal microvascular abnormalities and diabetic papillopathy from neovascularizations. Notably, however, FA and SS-OCTA VRI slab images demonstrated differences in identification efficacy in cases of small and flat neovascularizations. Further exploration of SS-OCTA technology is warranted to address this issue.

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.

Quantifying vascular density and morphology using different swept-source optical coherence tomography angiographic scan patterns in diabetic retinopathy.

AIMS: To evaluate quantitative metrics of the retinal microvasculature in eyes with diabetic retinopathy (DR) using various en face swept-source optical coherence tomography angiography (SS-OCTA) image sizes. METHODS: Non-segmented and segmented images were acquired using an SS-OCTA device (PLEX Elite 9000; Carl Zeiss Meditec, Dublin, California, USA). The scanning protocols included the 3×3 mm, 6×6 mm and 12×12 mm fields of view. Quantitative analysis of the perfusion density (PD), vessel length density (VLD) and fractal dimension (FD) was performed. The area under the receiver operating characteristic curve was estimated to assess the ability of each image size to predict DR. RESULTS: This prospective, cross-sectional study included 60 eyes, (non-DR, 13 eyes; non-proliferative DR (NPDR), 24 eyes; proliferative DR (PDR), 23 eyes) of 46 patients with diabetes and 21 eyes of 16 healthy individuals. In the 12×12 mm images, the PD of healthy individuals was significantly greater than that of patients with NPDR or PDR for all layers (NPDR, p<0.05; PDR, p<0.001 0.001; FD, p<0.001) or PDR (VLD, p<0.001; FD, p<0.001 for all layers). The results were similar for the 3×3 mm and 6×6 mm images. Overall, PD, VLD and FD progressively decreased with worsening DR severity in segmented and non-segmented layers for all SS-OCTA scan sizes. For detecting DR, 3×3 mm images best predicted DR for all evaluated quantitative parameters. CONCLUSIONS: Vascular changes in DR can be monitored in detail through quantitative evaluations that combine different SS-OCTA scan sizes and parameters.

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.

Assessment of diabetic retinopathy using two ultra-wide-field fundus imaging systems, the Clarus® and Optos™ systems.

BACKGROUND: The ability to image wide fundus fields and to conduct swift, non-invasive examinations is increasingly important with the escalation in patients with diabetic retinopathy (DR). METHODS: Fifty eyes of 28 consecutive patients with DR were examined in this prospective observational study. A total of 46 eyes, 25 right and 21 left eyes, of 27 patients (male, 19; female, 8) were ultimately included in the analysis. All patients underwent comprehensive ophthalmological examination. A single image each was obtained using two ultra-wide-field (UWF) imaging systems: Optos® (Optos Carfornia®, Optos PLC, Dunfermline, United Kingdom) and Clarus™ (CLARUS 500™, Carl Zeiss Meditec Inc., Californea, USA), without mydriasis. The total retinal area captured and the obscured retinal area were compared between the two systems using nonparametric Wilcoxon matched-pairs signed-rank analysis. Early Treatment of Diabetic Retinopathy Study (ETDRS) and International Clinical DR severity were analyzed by κ statistics. RESULTS: The Optos® allowed capture of larger areas of the fundus than the Clarus™ (465 ± 117 vs. 243 ± 39 disc areas, P < 0.0001). In 85% (39/46) of Optos® images and 7% (3/46) of Clarus™ images, a slightly obscured area was observed within the ETDRS-7 field area. κ values for ETDRS DR severity and International Clinical DR severity between the Optos® and Clarus™ images were 0.88 and 0.79, respectively. Severity was higher according to Clarus™ images in two eyes in which the ETDRS DR severity grading differed between the systems. Severity was higher in four Clarus™ images and in a single Optos® image in five eyes in which the International Clinical DR severity grading differed between the systems. CONCLUSION: The Optos® and Clarus™ UWF retinal imaging systems were useful for examining eyes with DR, using single images obtained without mydriasis. The systems were both generally consistent in assessing DR severity, with some partial discrepancies. It is important to understand the characteristics of each respective UWF retinal imaging system when using them to assess DR.

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.

Wide-field en face swept-source optical coherence tomography angiography using extended field imaging in diabetic retinopathy.

AIMS: To examine the feasibility of wide-field en face swept-source optical coherence tomography angiography (SS-OCTA) with extended field imaging (EFI) for evaluation of the retinal vasculature in diabetic retinopathy (DR). METHODS: This study included 37 eyes of 27 patients (age, 65±10 years; male patients, 18; female patients, 9) with DR. All patients underwent comprehensive ophthalmological examination, including OCTA and fluorescein angiography (FA). The imaging methods were compared for visible field of view, presence and extent of non-perfused areas (NPAs), presence and number of new blood vessels (NVs), vessel density (VD) and patient comfort level measured by Visual Analogue Scale. RESULTS: SS-OCTA with EFI allowed capture of larger areas (by 1.80±0.18 times on average) of the fundus than SS-OCTA without EFI. Compared with FA, the sensitivities of SS-OCTA with EFI for detection of NPAs and NVs were 96% and 79%, respectively, with specificities of 100% and 96%, respectively. There was no significant difference in extent of NPAs (61.2±45.8 vs 61.5±55.0 disc areas, P=0.99) or number of NVs (1.5±3.3 vs 0.9±1.8, P=0.68) between FA and SS-OCTA with EFI. VD showed significantly lower values in EFI SS-OCTA than in those acquired without EFI (31.6%±4.3% vs 34.2%±4.3%, P<0.001). Wide-field OCTA with EFI was significantly more comfortable for patients than FA (P<0.001). CONCLUSIONS: SS-OCTA with EFI allows acquisition of wide-field en face images of the retinal vasculature in patients with DR, with greater patient comfort than FA.

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.

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.

Delineation of capillary dropout in the deep retinal capillary plexus using optical coherence tomography angiography in a patient with Purtscher's retinopathy exhibiting normal fluorescein angiography findings: a case report.

BACKGROUND: Fat embolism in the deep retinal capillary plexus is one of the reported mechanisms underlying central/paracentral scotoma in patients with Purtscher's retinopathy. Here we report the clear delineation of capillary dropout in the deep capillary plexus using optical coherence tomography angiography (OCTA) in a chronic case of unexplained scotoma that developed after femoral fracture. The patient exhibited normal fluorescein angiography (FA) findings and a normal retinal appearance. CASE PRESENTATION: A 42-year-old Japanese man with a history of bilateral, unexplained paracentral scotoma that developed after femoral fracture and pulmonary fat embolism due to a car accident 20 years ago was referred to our outpatient clinic. Initial ophthalmological examination revealed unremarkable retinal findings. Goldmann perimetry, FA, and full field electroretinography showed no pathological changes. Although fat embolism in the retinal vasculature was suspected, psychosomatic visual field defects could not be ruled out. We performed OCTA, which clearly delineated capillary dropout in the deep retinal capillary plexus. A final diagnosis of paracentral acute middle maculopathy secondary to Purtscher's retinopathy was made on the basis of this finding. CONCLUSIONS: Our findings suggest that OCTA clearly and noninvasively delineates the deep retinal capillary plexus and the superficial capillary plexus. Because conventional FA provides limited depth resolution, capillary dropout restricted within the deep capillary plexus cannot be detected, particularly when the superficial capillary plexus is well preserved. Thus, OCTA can be a useful tool for the detection of capillary dropout in the deep retinal capillary plexus.

Effect of leaking capillaries and microaneurysms in the perifoveal capillary network on resolution of macular edema by anti-vascular endothelial growth factor treatment.

PURPOSE: To investigate the effect of leaking capillaries and microaneurysms (MAs) in the perifoveal capillary network (PCN) on the treatment of fovea-involving macular edema (ME) secondary to branch retinal vein occlusion (BRVO) by intravitreal ranibizumab (IVR) injections combined with focal, grid, and scatter laser photocoagulation. METHODS: Retrospective comparative case series. The MA (+) group consisted of 12 patients with leaking MAs in the PCN and the MA (-) group contained 11 patients without. At 6 months following the initial IVR injection, best corrected visual acuity (BCVA) was evaluated as the primary outcome. Secondary outcomes included central macular thickness (CMT) and the number of IVR injections performed in a pro re nata (PRN) regimen when CMT was ≥300 µm and vision deteriorated by 0.1 logMAR or greater. RESULTS: Mean BCVA improved by 0.30 ± 0.25 logMAR in the MA (-) group and 0.28 ± 0.20 logMAR in the MA (+) group (both P < 0.0001). Mean CMT was reduced by 237.6 ± 221.4 µm (P < 0.0001) in the MA (-) and 158.2 ± 152.1 µm (P < 0.01) in the MA (+) group. The degrees of improvement in BCVA (P = 0.74) and CMT (P = 0.33) did not vary significantly between the groups. The mean number of additional IVR injections was significantly less in the MA (-) group than in the MA (+) group (2.2 ± 1.0 vs 3.0 ± 0.8; P = 0.04). CONCLUSIONS: Although leaking MAs and capillaries in the PCN did not adversely affect improvements in BCVA and CMT, these manifestations led to an increased number of IVR injections needed to sustain resolution of ME involving the fovea.

Pathophysiological function of endogenous calcitonin gene-related peptide in ocular vascular diseases.

Calcitonin gene-related peptide (CGRP; official name CALCA) has a variety of functions and exhibits both angiogenic and anti-inflammatory properties. We previously reported the angiogenic effects of the CGRP family peptide adrenomedullin in oxygen-induced retinopathy; however, the effects of CGRP on ocular angiogenesis remain unknown. Herein, we used CGRP knockout (CGRP(-/-)) mice to investigate the roles of CGRP in ocular vascular disease. Observation of pathological retinal angiogenesis in the oxygen-induced retinopathy model revealed no difference between CGRP(-/-) and wild-type mice. However, much higher levels of the CGRP receptor were present in the choroid than the retina. Laser-induced choroidal neovascularization (CNV), a model of exudative age-related macular degeneration, revealed more severe CNV lesions in CGRP(-/-) than wild-type mice, and fluorescein angiography showed greater leakage from CNV in CGRP(-/-). In addition, macrophage infiltration and tumor necrosis factor (TNF)-α production were enhanced within the CNV lesions in CGRP(-/-) mice, and the TNF-α, in turn, suppressed the barrier formation of retinal pigment epithelial cells. In vivo, CGRP administration suppressed CNV formation, and CGRP also dose dependently suppressed TNF-α production by isolated macrophages. From these data, we conclude that CGRP suppresses the development of leaky CNV through negative regulation of inflammation. CGRP may thus be a promising therapeutic agent for the treatment of ocular vascular diseases associated with inflammation.

En face swept-source optical coherence tomography detecting thinning of inner retinal layers as an indicator of capillary nonperfusion.

PURPOSE: To report en face swept-source optical coherence tomography (SS-OCT) as a noninvasive detection modality for regions of retinal layer thinning that are potential indicators of retinal nonperfusion areas (NPAs) in patients with branch retinal vein occlusion (BRVO). METHODS: Thirty-one eyes of 46 patients with BRVO showing a definite retinal NPA larger than 1 disc in diameter within the vascular arcades were included in this study. We calculated the overlapping correspondence ratio between presumed NPA, which appeared as a dark area in en face SS-OCT, and definite NPA in corresponding fluorescein angiography (FA) images. The correlation between brightness in en face SS-OCT images and corresponding ganglion cell complex (GCC) thickness determined by SD-OCT GCC maps was evaluated as well. RESULTS: Measured NPA size in FA and presumed NPA size in en face SS-OCT showed strong correlation (r = 0.746, p<0.001) and colocalization. Reliable agreement between the 2 methods was confirmed by size comparisons (p = 0.11), with an overlapping correspondence ratio of 0.73. CONCLUSIONS: The results suggest that en face SS-OCT is a noninvasive and relatively reliable method for delineating retinal thinning as an indicator of NPAs in eyes with BRVO. Because SS-OCT can be performed without mydriasis, this procedure may be an option for evaluating NPAs on a screening basis and during follow-up to reduce the number of FA examinations that carry very rare, but potentially fatal, allergic side effects.

Dynamics of macular hole closure in gas-filled eyes within 24 h of surgery observed with swept source optical coherence tomography.

BACKGROUND/AIMS: To investigate the dynamics of macular hole (MH) closure in gas-filled eyes starting 20 min after vitrectomy using swept source optical coherence tomography (SS-OCT). METHODS: Twenty consecutive eyes with MH underwent vitrectomy with internal limiting membrane peeling and gas tamponade. SS-OCT imaging was performed approximately 20 min after the operation, and then once a day, until MH closure was confirmed. The correlation between the base, top and minimum hole diameters and the duration required for MH closure was investigated. RESULTS: MH closure in gas-filled eyes was confirmed in 1 eye on day 0, 10 eyes on day 1, 2 eyes on day 2, and 3 eyes on day 3, at which times face-down posturing was discontinued without MH recurrence. SS-OCT revealed a distinct closure pattern within the first 24 h postoperatively. MHs closing by day 1 had a significantly smaller minimum diameter (312.5 ± 105.2 µm) than holes closing on day 2 or later (510.8 ± 153.5 µm; p = 0.019). CONCLUSIONS: SS-OCT enables tomographic images of MH in gas-filled eyes immediately postoperatively, thus permitting early discontinuation of, or no necessity for, face-down positioning upon confirmation of MH closure.

Pathophysiological roles of adrenomedullin-RAMP2 system in acute and chronic cerebral ischemia.

The accessory protein RAMP2 is a component of the CLR/RAMP2 dimeric adrenomedullin (AM) receptor and is the primary determinant of the vascular functionality of AM. RAMP2 is highly expressed in the brain; however, its function there remains unclear. We therefore used heterozygous RAMP2 knockout (RAMP2+/-) mice, in which RAMP2 expression was reduced by half, to examine the actions of the endogenous AM-RAMP2 system in cerebral ischemia. To induce acute or chronic ischemia, mice were subjected to middle cerebral artery occlusion (MCAO) or bilateral common carotid artery stenosis (BCAS), respectively. In RAMP2+/- mice subjected to MCAO, recovery of cerebral blood flow (CBF) was slower than in WT mice. AM gene expression was upregulated after infarction in both genotypes, but the increase was greater in RAMP2+/- mice. Pathological analysis revealed severe nerve cell death and demyelination, and a higher level of oxidative stress in RAMP2+/- mice. In RAMP2+/- mice subjected to BCAS, recovery of cerebral perfusion was slower and less complete than in WT mice. In an 8-arm radial maze test, RAMP2+/- mice required more time to solve the maze and showed poorer reference memory. They also showed greater reductions in nerve cells and less compensatory capillary growth than WT mice. These results indicate the AM-RAMP2 system works to protect nerve cells from both acute and chronic cerebral ischemia by maintaining CBF, suppressing oxidative stress, and in the case of chronic ischemia, enhancing capillary growth.