Long-term outcomes of intravitreal activated protein C injection for ischemic central retinal vein occlusion: an extension trial.

PURPOSE: Our previous 1-year pilot study evaluated the efficacy of intravitreally injected activated protein C (APC) in 10 eyes with ischemic central retinal vein occlusion (CRVO). The reperfusion of the areas of retinal nonperfusion (RNP) exceeded 50% of the baseline in five (50%) eyes 1 year after the APC injection. The current study evaluated the long-term efficacy and safety of intravitreal APC. METHODS: The 10 eyes in the pilot study were included in this study. Other treatments were administered at the physicians' discretion after the pilot study. We evaluated visual acuity (VA), central retinal thickness (CRT) and perfusion status, and adverse events and severity over the long term. RESULTS: The median follow-up was 60 months (range, 48-68 months). Compared with baseline, the post-treatment VA improved significantly (P < 0.001) from 1.39 to 1.06 logarithm of the minimum angle of resolution. The CRT improved significantly (P < 0.001) from 1090 to 195 µm at the last visit. The RNP areas decreased from an average 29.7 disc areas (DAs) at baseline to an average 16.5 DAs at the last examination (mean, 40 ± 6.5 months after the first APC treatment). No adverse events were related to intravitreal APC. CONCLUSION: No complications were associated with intravitreal APC, the clinical course improved, and improved RNP was maintained for the long term, suggesting that intravitreal APC may be an alternative treatment for CRVO.

Inverted internal limiting membrane insertion versus standard internal limiting membrane peeling for macular hole retinal detachment in high myopia: one-year study.

PURPOSE: The aim of this study was to investigate the efficacy of pars plana vitrectomy with inverted internal limiting membrane (ILM) insertion for macular hole retinal detachment (MHRD) in high myopia. METHODS: We studied 49 eyes of 49 consecutive patients who underwent vitrectomy for MHRD and were followed for more than 12 months postoperatively. Eyes that underwent vitrectomy with inverted ILM insertion from October 2013 to August 2015 were compared with eyes that underwent standard ILM peeling from October 2006 to September 2013. Macular hole closure rate, retinal reattachment, and postoperative visual acuity (VA) at 6 and12 months were retrospectively evaluated. RESULTS: This series included 13 eyes in the inverted ILM insertion group and 36 eyes in the standard ILM peeling group. The MH closure rate was significantly better in the inverted ILM group (92 vs 39%) (P = 0.003). The initial and final retinal reattachment rates (92% vs. 86%, and 100% in both groups, respectively) did not differ significantly between groups. Although the mean preoperative VA did not differ significantly between the groups, postoperative VA tended to be better in the inverted ILM group at 12 months (P = 0.059). The rate of visual improvement of three or more lines in the inverted ILM insertion group (85%) was higher than that in the standard ILM peeling group (47%) at 12 months (P = 0.045). CONCLUSION: Compared to conventional ILM peeling, inverted ILM insertion has a higher MH closure rate and tendency of better postoperative VA in patients with MHRD.

Chronic photo-oxidative stress and subsequent MCP-1 activation as causative factors for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Although pathogenic factors, such as oxidative stress, inflammation and genetics are thought to contribute to the development of AMD, little is known about the relationships and priorities between these factors. Here, we show that chronic photo-oxidative stress is an environmental factor involved in AMD pathogenesis. We first demonstrated that exposure to light induced phospholipid oxidation in the mouse retina, which was more prominent in aged animals. The induced oxidized phospholipids led to an increase in the expression of monocyte chemoattractant protein-1, which then resulted in macrophage accumulation, an inflammatory process. Antioxidant treatment prevented light-induced phospholipid oxidation and the subsequent increase of monocyte chemoattractant protein-1 (also known as C-C motif chemokine 2; CCL2), which are the beginnings of the light-induced changes. Subretinal application of oxidized phospholipids induced choroidal neovascularization, a characteristic feature of wet-type AMD, which was inhibited by blocking monocyte chemoattractant protein-1. These findings strongly suggest that a sequential cascade from photic stress to inflammatory processes through phospholipid oxidation has an important role in AMD pathogenesis. Finally, we succeeded in mimicking human AMD in mice with low-level, long-term photic stress, in which characteristic pathological changes, including choroidal neovascularization formation, were observed. Therefore, we propose a consecutive pathogenic pathway involving photic stress, oxidation of phospholipids and chronic inflammation, leading to angiogenesis. These findings add to the current understanding of AMD pathology and suggest protection from oxidative stress or suppression of the subsequent inflammation as new potential therapeutic targets for AMD.

Fovea-Sparing versus Standard Internal Limiting Membrane Peeling for Myopic Traction Maculopathy: A Study of 102 Consecutive Cases.

PURPOSE: To investigate the long-term outcomes of pars plana vitrectomy (PPV) with fovea-sparing internal limiting membrane (ILM) peeling (FSIP) and standard ILM peeling for myopic traction maculopathy (MTM). DESIGN: Retrospective case series. PARTICIPANTS: A total of 102 eyes of 96 consecutive patients who underwent primary PPV for MTM and were followed up for at least 12 months. METHODS: We compared the outcomes of eyes that underwent vitrectomy with FSIP from October 2012 to March 2017 with those of eyes that underwent vitrectomy with standard ILM peeling from June 2008 to September 2012. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) at 12 months and the final follow-up visit after surgery, time to MTM resolution, and postoperative complications such as macular hole (MH) formation. RESULTS: There were 26 and 76 eyes in the FSIP and standard ILM peeling groups, respectively. In both groups, the mean visual acuity (VA) at the 12-month follow-up was significantly improved relative to the mean preoperative VA (P < 0.001 for both groups). The preoperative and postoperative BCVA (logarithm of the minimum angle of resolution) showed no significant between-group differences (preoperative: 0.60±0.35 in the FSIP group and 0.61±0.39 in the standard ILM peeling group, P = 0.935; postoperative BCVA: 0.32 ± 0.43 in the FSIP group and 0.37 ± 0.38 in the standard ILM peeling group, P = 0.281). The mean time to the resolution of foveal retinal detachment and schisis was also comparable between groups (8.9 ± 4.8 months in the FSIP group and 6.9 ± 4.6 months in the standard ILM peeling group, P = 0.084). None of the eyes in the FSIP group and 6 eyes (8%) in the standard ILM peeling group developed postoperative MH. Consequently, the BCVA at 12 months deteriorated by 3 or more lines for 4 eyes (5%) in the standard ILM peeling group; this deterioration was not observed for any eye in the FSIP group. Risk factors for postoperative MH formation were worse preoperative visual acuity (P = 0.035) and thinner choroidal thickness (P = 0.025). CONCLUSIONS: The visual and anatomic improvements after vitrectomy with FSIP may be comparable to those after vitrectomy with standard ILM peeling, with FSIP showing the ability to prevent postoperative MH formation and a consequent impairment in vision.

Activated Protein C for Ischemic Central Retinal Vein Occlusion: One-Year Results.

Intravitreally administered activated protein C in 10 eyes with ischemic central retinal vein occlusion significantly improved macular edema; in 5 eyes, the reperfusion of the retinal nonperfused areas exceeded 50% of baseline.

[Influence of vitrectomy for diabetic retinopathy on health-related quality of life].

PURPOSE: To evaluate the vision-related quality of life (QOL) in patients undergoing vitrectomy for diabetic retinopathy with the Japanese version of the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). SUBJECTS AND METHODS: Subjects were 87 patients undergoing vitrectomy for diabetic retinopathy of vitreous hemorrhage, macular edema, or fibrovascular membrane, only for the subject eye, or for subjects undergoing vitrectomy for the fellow eye within 6 months or later. The VFQ-25 date was recorded one month before and 6 months after the vitrectomy. The VFQ-25 data were compared before and after the vitrectomy. The subjects were classified by the pathological condition: 41 eyes with vitreous hemorrhage, 28 eyes with macular edema, and 18 eyes with fibrovascular membrane. RESULTS: The average VFQ-25 scores of all the patients increased in almost all of the 12 subscales. Vitrectomy for vitreous hemorrhage was most effective in improving the VFQ-25 score, in improving 10 of the 12 subscales in the VFQ-25, and in increasing VFQ-25 scores to almost the same level as in phacoemulsification and foldable intraocular lens implantation for cataract patients in both eyes. CONCLUSION: NEI VFQ-25 quantitatively clarified that vitrectomy for diabetic retinopathy is effective in increasing the QOL of diabetic retinopathy patients.

[Evaluation of the efficacy of intravitreal gas injection for submacular hemorrhages].

PURPOSE: To evaluate the efficacy of intravitreal gas injection for submacular hemorrhages(SMH). PATIENTS AND METHODS: The records of 29 patients with SMH, who were treated by pneumatic displacement with expansile gas, were reviewed retrospectively. RESULT: In observable cases, SMH had started moving within five days after the procedure. After 6 months visual acuity had been improved 2 or more lines in 23 eyes(79%). The causes of SMH were age-related macular degeneration (17 eyes) and microaneurysm (12 eyes). The larger the size of SMH, had the greater the risk of developing vitreous hemorrhage. Twelve eyes of the 29 eyes required vitrectomy owing to vitreous hemorrhage, insufficient removal of SMH, etc. but this pneumatic procedure often eliminated the need for vitrectomy. The visual acuity of the patients with additional vitrectomy was improved with only pneumatic displacement. None of the patients had serious complications with this pneumatic procedure and the vitrectomy. CONCLUSION: The first choice for SMH is intravitreal gas injection which saves foveal function, and improves the prognosis for better vision.

[Efficacy of vitreous surgery for uveal effusion syndrome].

PURPOSE: To evaluate the efficacy of pars plana vitrectomy for uveal effusion syndrome retrospectively. SUBJECTS AND METHODS: Six patients (six eyes) with uveal effusion syndrome(UE) underwent vitrectomy followed by internal drainage of subretinal fluid, fluid-gas exchange, and pan-retinal photocoagulation. Three of these cases with nanophthalmos underwent silicone oil injection. RESULTS: The retina became reattached in all cases. The silicone oil was not removed in two of the three cases with nanophthalmic eyes. Two cases of the three cases with nanophthalmic eyes needed to perform full thickness sclerostomy additionally, and in one case subchoroidal hemorrhage occurred. The visual acuity finally improved in five out of the six eyes. CONCLUSIONS: In cases of uveal effusion without nanophthalmic, vitrectomy hastens quick reattachment of the retina and may result in better visual outcome. But in cases of nanophthalmic eyes, it would be better to perform sclerostomy first.

Posterior vitreous detachment and macular hole formation in myopic foveoschisis.

PURPOSE: To report two cases of macular hole (MH) associated with myopic foveoschisis (MF). DESIGN: Interventional case report. METHODS: Two women presented with metamorphopsia. Preoperative optical coherence tomography (OCT) showed an MH and MF. We performed vitrectomy, internal limiting membrane (ILM) peeling and gas tamponade. RESULTS: Preoperative OCT examination and intraoperative microscopic observation revealed partial posterior vitreous detachment (PVD) at the posterior retina and vitreous strands adhering to the edge of the MHs. The MF resolved in both patients, but the MHs remained open postoperatively. CONCLUSIONS: Although the contribution of tangential traction cannot be excluded, the mechanism of MH formation in eyes with MF may be anteroposterior traction via abnormal vitreofoveal adhesion resulting from partial PVD.

Matched control study of visual outcomes after arteriovenous sheathotomy for branch retinal vein occlusion.

BACKGROUND: The purpose of this study was to evaluate visual outcomes of arteriovenous sheathotomy for macular edema due to branch retinal vein occlusion (BRVO). METHODS: The medical records of 45 eyes from 45 patients who had undergone vitrectomy surgery with arteriovenous sheathotomy for BRVO were studied. Forty-five eyes of 45 patients with a BRVO but without intervention were studied as the control group. The best-corrected visual acuity and central macular thickness were compared between the two groups at baseline and at 1, 3, 6, and 12 months postoperatively. RESULTS: Improvement of best-corrected visual acuity was 0.42 logarithm of the minimum angle of resolution (logMAR) units in the sheathotomy group and 0.22 logMAR units in the control group (P=0.007). The mean postoperative central macular thickness was significantly thinner in the sheathotomy group at 1 month (P=0.01), but not at 3, 6, and 12 months (P=0.75, P=0.81, and P=0.46, respectively). Improvement of best-corrected visual acuity at 12 months was significantly correlated with baseline best-corrected visual acuity, age, duration of symptoms, and sheathotomy (P<0.05). CONCLUSION: Arteriovenous sheathotomy for BRVO improves best-corrected visual acuity significantly more than the natural course of the BRVO disease process.

Direct photocoagulation to leakage points to treat chronic macular edema associated with branch retinal vein occlusion: a pilot study.

SUMMARY STATEMENT: Direct photocoagulation reduces the central foveal thickness (CFT) in cases with chronic branch retinal vein occlusion (BRVO) of longer than 12 months duration. Photo-coagulation might be effective for chronic macular edema due to branch retinal vein occlusion. BACKGROUND: The aim was to investigate the effect of direct photocoagulation for treating chronic macular edema associated with BRVO. METHODS: This study was a noncomparative, pilot interventional case series. We examined the CFT and best-corrected visual acuity over 6 months in patients with BRVO treated with direct photocoagulation. RESULTS: Sixteen eyes of 16 patients had been treated with direct photocoagulation (mean follow-up period, 20.5 months). The mean CFT decreased significantly (P<0.001) between the baseline (465 µm) and the final visit (304 µm). The mean (logarithm of the minimum angle of resolution equivalent) best-corrected visual acuity at the baseline was 0.39 and improved significantly (P<0.001) to 0.20 at the final visit. CONCLUSION: Direct photocoagulation to leakage points is beneficial for treating chronic macular edema associated with chronic BRVO of longer than 12 months duration.

Rigid gas-permeable contact lens-assisted cataract surgery in patients with severe keratoconus.

We describe rigid gas-permeable (RGP) contact lens-assisted cataract surgery in patients with severe keratoconus. During cataract surgery in cases with severe keratoconus, the intraocular images are distorted and visual perspective is lost because of irregular corneal astigmatism. Poor visibility can lead to complications, including posterior capsule rupture and corneal endothelial cell damage. To overcome these problems, an RGP contact lens was placed on the cornea in 2 cases. The image distortion decreased markedly, and the visual perspective improved. Intraocular manipulations such as irrigation/aspiration were performed safely. Improvement in transillumination led to good visualization of the anterior and posterior capsules. No intraoperative or postoperative complications developed in either case. This technique provided excellent visualization during cataract surgery in patients with severe keratoconus.

Relationship between grades of macular perfusion and foveal thickness in branch retinal vein occlusion.

BACKGROUND: To study the relationship between retinal perfusion around the macula and the foveal thickness in branch retinal vein occlusion (BRVO). METHODS: Seventy-four eyes of 74 consecutive patients with BRVO were enrolled. We developed a new grading system to evaluate the status of retinal perfusion around the macula in three grades: full perfusion area (FPA), partial perfusion area (PPA), and nonperfusion area (NPA), using fluorescein angiography. The correlation was assessed between these grades and the central foveal thickness (CFT) measured by optical coherence tomography. We also determined the area with the closest correlation between the perfusion status and the foveal thickness by comparing the correlation coefficient in areas of 1-, 2-, and 3-disc diameter (DD) horizontal hemicircles centered at the fovea. The correlation was determined between the extent of each perfusion grade and CFT. RESULTS: We found a significant negative correlation between the CFT and the FPA (r = 0.31, P = 0.006) and a significant positive correlation between the CFT and the PPA (r = 0.45, P < 0.001) in the three areas. The most significant correlations were found in the 2-DD area. Interestingly, the NPA has not correlated with the foveal thickness in any areas. CONCLUSION: The areas of partial but not complete capillary loss seem to be responsible for the macular edema associated with BRVO. Treatments targeting leakage from the dilated capillaries in the PPA should be investigated.

Low-dose lipopolysaccharide pretreatment suppresses choroidal neovascularization via IL-10 induction.

Recent studies have suggested that some kinds of microbial infection may have a crucial role in the development of many diseases such as autoimmune diseases and certain types of cancer. It has been reported that some chronic infections, such as Chlamydia pneumoniae, and immunological dysfunctions are associated with age-related macular degeneration (AMD), a leading cause of blindness. To evaluate the association between systemic low-level inflammation induced by infection and AMD pathogenesis, we investigated whether intraperitoneal injection of lipopolysaccharide (LPS) can modulate the development of laser-induced choroidal neovascularization (CNV), a key feature of AMD. Contrary to our expectations, the sizes of CNV in mice with LPS pretreatment were approximately 65% smaller than those of the control mice. After LPS pretreatment, serum IL-10 concentration and IL-10 gene expression in peritoneal macrophages and in the posterior part of the eye increased. Peritoneal injection of anti-IL10 antibody reduced CNV suppression by LPS pretreatment. Moreover, adoptive transfer of the resident peritoneal macrophages from LPS-treated mice into control littermates resulted in an approximately 26% reduction in the size of CNV compared with PBS-treated mice. We concluded that CNV formation was suppressed by low-dose LPS pretreatment via IL-10 production by macrophages.

Commercially available rigid gas-permeable contact lens for protecting the cornea from drying during vitrectomy with a wide viewing system.

PURPOSE: We evaluated the usefulness of commercially available materials for protecting the cornea from drying during vitrectomy with a wide-angle viewing system. METHODS: THREE VITREORETINAL SURGEONS EVALUATED FUNDUS VISIBILITY DURING VITRECTOMY ON THE IMAGES OF FIVE STUDY MATERIALS USED ON THE CORNEA: balanced saline solution, a viscoelastic agent, a vitrectomy contact lens, a rigid gas permeable (RGP) contact lens, and a soft contact lens. Fundus visibility was graded using the following scale: grade 1, unclear; grade 2, slightly unclear; grade 3, clear; and grade 4, very clear. RESULTS: RESPECTIVE SCORES FOR EACH MATERIAL USED DURING CORE VITRECTOMY AND MEMBRANE REMOVAL WERE: balanced saline solution, 3.3/3.3; viscoelastic agent, 3.8/3.3; vitrectomy contact lens, 3.3/4.0; RGP contact lens, 4.0/3.9; soft contact lens, 1.1/not applicable. CONCLUSION: The RGP contact lens provided visibility similar to or clearer than that obtained with other methods. Because of its ease of use and lower cost, use of the RGP contact lens is ideal during vitrectomy performed with a wide-angle viewing system.

Simultaneous intravitreal injection of triamcinolone acetonide and tissue plasminogen activator for central retinal vein occlusion: a pilot study.

PURPOSE: To evaluate the efficacy and safety of simultaneous intravitreal injection of triamcinolone acetonide (TA) and tissue plasminogen activator (tPA) for macular oedema associated with central retinal vein occlusion (CRVO). METHODS: Twenty eyes of 20 patients with CRVO were enrolled. A mixture of TA (4 mg) and tPA (25 µg) was injected into the vitreous of 20 eyes with CRVO. Best corrected visual acuity (BCVA) and macular thickness before and 1, 3, 6 and 12 months after the procedure were measured. RESULTS: The BCVA improved three lines or more in 65%, 55%, 55% and 53% of eyes and the mean macular thickness decreased from 1072 µm to 455, 450, 480 and 409 µm (p<0.001) at 1, 3, 6 and 12 months, respectively. Fifteen (75%) of the 20 eyes required at least one additional injection to prevent a recurrence of macular oedema. The intraocular pressure increased in four eyes. CONCLUSION: Overall, intravitreal injection of the TA/tPA mixture improved the BCVA by three lines or more in at least 50% of eyes and decreased the mean macular thickness at four time points without serious side effects. A randomised clinical trial is necessary to evaluate the efficacy of this treatment.

Suppression and regression of choroidal neovascularization in mice by a novel CCR2 antagonist, INCB3344.

PURPOSE: To investigate the effect of an intravitreally administered CCR2 antagonist, INCB3344, on a mouse model of choroidal neovascularization (CNV). METHODS: CNV was induced by laser photocoagulation on Day 0 in wild type mice. INCB3344 or vehicle was administered intravitreally immediately after laser application. On Day 14, CNV areas were measured on retinal pigment epithelium (RPE)-choroid flat mounts and histopathologic examination was performed on 7 µm-thick sections. Macrophage infiltration was evaluated by immunohistochemistry on RPE-choroid flat mounts and quantified by flow cytometry on Day 3. Expression of vascular endothelial growth factor (VEGF) protein in RPE-choroid tissue was examined by immunohistochemistry and ELISA, VEGF mRNA in sorted macrophages in RPE-choroid tissue was examine by real-time PCR and expression of phosphorylated extracellular signal-regulated kinase (p-ERK 1/2) in RPE-choroid tissue was measured by Western blot analysis on Day 3. We also evaluated the efficacy of intravitreal INCB3344 to spontaneous CNV detected in Cu, Zn-superoxide dismutase (SOD1) deficient mice. Changes in CNV size were assessed between pre- and 1week post-INCB3344 or vehicle administration in fundus photography and fluorescence angiography (FA). RESULTS: The mean CNV area in INCB3344-treated mice decreased by 42.4% compared with the vehicle-treated control mice (p<0.001). INCB3344 treatment significantly inhibited macrophage infiltration into the laser-irradiated area (p<0.001), and suppressed the expression of VEGF protein (p = 0.012), VEGF mRNA in infiltrating macrophages (p<0.001) and the phosphorylation of ERK1/2 (p<0.001). The area of spontaneous CNV in Sod1⁻/⁻ mice regressed by 70.35% in INCB3344-treated animals while no change was detected in vehicle-treated control mice (p<0.001). CONCLUSIONS: INCB3344 both inhibits newly forming CNV and regresses established CNV. Controlling inflammation by suppressing macrophage infiltration and angiogenic ability via the CCR-2/MCP-1 signal may be a useful therapeutic strategy for treating CNV associated with age-related macular degeneration.