Ranibizumab treatment improves diabetic macular oedema without influencing retinal oximetry parameters.

PURPOSE: To evaluate the effect of ranibizumab on retinal oximetry in eyes with diabetic macular oedema (DME). METHODS: In this prospective interventional study, 30 eyes (30 patients) with DME were treated with three-monthly intravitreal ranibizumab injections, followed by pro re nata administration for 12 months. Retinal oximetry was performed using an Oxymap T1. RESULTS: The mean number of injections was 6.6 ± 2.5. No adverse event was observed throughout the study period. Ranibizumab treatments for 12 months improved the macular oedema (p = 0.002) and achieved a recovery of visual acuity (VA; p = 0.011). However, oxygen saturation levels in the major retinal blood vessels, either the arteries or the veins, remained unchanged during the observational period. Arterial oxygen saturation was 100.3 ± 9.4% before treatment and 100.9 ± 10.7% (p = 0.698) at 6 months. Venous oxygen saturation was 56.4 ± 8.9% before treatment and 55.6 ± 8.6% (p = 0.529) at 6 months. In addition, there were no significant changes in diameters of the major retinal arteries and veins. Greater improvement of VA at 12 months was correlated with a smaller number of ranibizumab injections (r = 0.459, p = 0.011). The number of ranibizumab injections during these 12 months correlated with an increased baseline central retinal thickness (r = 0.385, p = 0.035). CONCLUSION: Ranibizumab treatments for DME improved the macular oedema and achieved VA recovery, but no changes were noted in the retinal oxygen saturation.

Retinal oximetry in branch retinal vein occlusion.

PURPOSE: To measure retinal oxygen saturation (SO2 ) in eyes with branch retinal vein occlusion (BRVO). METHODS: Retinal oximetry was performed using the Oxymap T1 retinal oximeter in 50 eyes (50 patients) with resolved BRVO. SO2 was calculated in each major retinal artery and vein in four quadrants. The superior or inferior hemisphere with BRVO was categorized as the affected hemisphere and the other as the unaffected hemisphere. RESULTS: Oxymap T1 allowed us to measure SO2 in major retinal vessels. Both arterial and venous SO2 in the affected hemisphere were significantly higher than those in the unaffected hemisphere. However, there was no significant difference in arteriovenous (A-V) difference in SO2 between the affected and unaffected hemispheres. Of the 50 included eyes, 32 had non-ischemic BRVO and 18 had ischemic BRVO. In the affected hemisphere, arterial SO2 was significantly higher in ischemic BRVO (106.9 ± 8.8%) than in non-ischemic BRVO (101.3 ± 9.2%, p = 0.044). There were no significant differences in venous SO2 between non-ischemic and ischemic BRVO. Consequently, the A-V difference in SO2 was significantly higher in ischemic BRVO (51.9 ± 13.9%) than in non-ischemic BRVO (43.4 ± 11.5%, p = 0.028). In multiple regression analysis, the type of perfusion (non-ischemic or ischemic) had associations with arterial SO2 (ß = 0.365, p = 0.013) and with A-V differences in SO2 in the affected hemisphere (ß = 0.406, p = 0.006). CONCLUSION: In ischemic BRVO, arterial SO2 and the A-V difference in SO2 in the affected hemisphere were significantly higher than in non-ischemic BRVO.

Metamorphopsia associated with central retinal vein occlusion.

This prospective study aimed to investigate metamorphopsia in eyes with central retinal vein occlusion (CRVO) and included 28 eyes (28 patients) with unilateral CRVO that had macular edema (ME) in the acute phase. The ME was treated with anti-vascular endothelial growth factor agents. At baseline and at 1 and 6 months after initiation of treatment, quantitative measurements of metamorphopsia were performed using M-CHARTS and the retinal morphologic changes were examined by optical coherence tomography. At baseline, metamorphopsia was detected on M-CHARTS in 14 (50.0%) eyes. The mean M-CHARTS score was 0.37 ± 0.53. At 1 month and 6 months after initiation of treatment, there was substantial resolution of ME and significant recovery of visual acuity. In contrast, metamorphopsia was still detected in 16 eyes at 6 months; the mean M-CHARTS scores were 0.29 ± 0.37 at 1 month and 0.32 ± 0.38 at 6 months, and had not significantly improved from baseline (p = 0.580, and p = 0.604, respectively). Although the M-CHARTS score at 6 months was associated with the baseline M-CHARTS score (p = 0.004), it did not have any associations with morphologic parameters at baseline. However, the M-CHARTS score at 6 months was significantly associated with foveal photoreceptor status, height of serous detachment, and parafoveal thickening at 1 month. Metamorphopsia associated with CRVO could be quantified using M-CHARTS, and often persisted in contrast with the recovery of visual acuity and resolution of ME after treatment with anti-vascular endothelial growth factor agents.

The effect of vitreomacular and cataract surgery on oxygen saturation in retinal vessels.

PURPOSE: To evaluate the effects of vitreomacular and cataract surgery on retinal oximetry in vitreomacular disease. PATIENTS AND METHODS: Thirty-eight eyes with epiretinal membrane (ERM) and 15 with idiopathic macular hole (MH) underwent 25 gauge pars plana vitrectomy combined with cataract surgery and intraocular lens implantation. Retinal oximetry was performed using the Oxymap T1 before, 1 month, and 6 months after surgery. Oxymap T1 simultaneously captures monochrome images of the fundus at two different wavelengths of light. Built-in Oxymap Analyzer software measures the oxygen saturation and vessel diameter. RESULTS: Mean arterial oxygen saturation significantly increased from 96.8%±6.2% to 100.2%±5.8% at 1 month and to 99.6%±5.8% at 6 months after surgery (P<0.01). Mean venous oxygen saturation also significantly increased from 54.6%±7.5% to 61.2%±6.4% at 1 month and to 62.6%±5.9% at 6 months after surgery (P<0.01). Mean arteriovenous (A-V) difference decreased from 42.2%±6.6% to 39.0%±7.8% at 1 month and to 37.0%±6.9% at 6 months after surgery (P<0.01). The ERM and MH groups showed similar changes in retinal oxygen saturation. However, there were no significant changes in the caliber of major retinal vessels after surgery (from 125.2±15.2 µm to 124.0±15.4 µm in artery, from 168.7±14.6 µm to 169.8±14.6 µm in vein). CONCLUSION: Oxymap T1 was able to measure the increase in oxygen saturation in retinal arteries and veins, which led to a decrease in the A-V difference in oxygen saturation after vitrectomy combined with cataract surgery.

ASSOCIATION BETWEEN PARAFOVEAL CAPILLARY NONPERFUSION AND MACULAR FUNCTION IN EYES WITH BRANCH RETINAL VEIN OCCLUSION.

PURPOSE: To investigate the parafoveal perfusion status of the superficial and deep capillary layer in eyes with resolved branch retinal vein occlusion, and to study its effects on retinal sensitivity. METHODS: In 27 enrolled eyes (27 patients) with resolved branch retinal vein occlusion, superficial and deep capillaries in the macular area (3- × 3-mm, centered on the fovea) were examined with optical coherence tomography angiography. Retinal sensitivity was examined with fundus-monitored microperimetry. RESULTS: Optical coherence tomography angiography clearly showed the parafoveal superficial and deep capillaries individually. On the affected side of retina, 25 eyes (92.6%) showed capillary nonperfusion; 23 (85.2%) in the superficial layer and 22 (81.5%) in the deep layer. Capillary nonperfusions of both layers frequently overlapped and appeared to be connected with each other. Mean (±SD) retinal sensitivity at the superficial capillary nonperfusion was 19.2 ± 6.3 dB, significantly lower than that at the superficial capillary perfusion (24.4 ± 2.8 dB, P < 0.001). Similarly, mean retinal sensitivity at the deep capillary nonperfusion was 20.8 ± 5.0 dB, significantly lower than that at deep capillary perfusion (24.3 ± 2.8 dB, P = 0.0016). Mean retinal sensitivity with superficial capillary nonperfusion was significantly lower than that with deep capillary nonperfusion (P = 0.0226). CONCLUSION: Optical coherence tomography angiography visualized parafoveal capillary nonperfusion in superficial and deep layers individually in eyes with resolved branch retinal vein occlusion. Retinal sensitivity was significantly reduced at these capillary nonperfusions.

Metamorphopsia Associated with Branch Retinal Vein Occlusion.

PURPOSE: To apply M-CHARTS for quantitative measurements of metamorphopsia in eyes with acute branch retinal vein occlusion (BRVO) and to elucidate the pathomorphology that causes metamorphopsia. METHODS: This prospective study consisted of 42 consecutive patients (42 eyes) with acute BRVO. Both at baseline and one month after treatment with ranibizumab, metamorphopsia was measured with M-CHARTS, and the retinal morphological changes were examined with optical coherence tomography. RESULTS: At baseline, metamorphopsia was detected in the vertical and/or horizontal directions in 29 (69.0%) eyes; the mean vertical and horizontal scores were 0.59 ± 0.57 and 0.52 ± 0.67, respectively. The maximum inner retinal thickness showed no association with the M-CHARTS score, but the M-CHARTS score was correlated with the total foveal thickness (r = 0.43, p = 0.004), the height of serous retinal detachment (r = 0.31, p = 0.047), and the maximum outer retinal thickness (r = 0.36, p = 0.020). One month after treatment, both the inner and outer retinal thickness substantially decreased. However, metamorphopsia persisted in 26 (89.7%) of 29 eyes. The posttreatment M-CHARTS score was not correlated with any posttreatment morphological parameters. However, the posttreatment M-CHARTS score was weakly correlated with the baseline total foveal thickness (r = 0.35. p = 0.024) and closely correlated with the baseline M-CHARTS score (r = 0.78, p < 0.001). CONCLUSIONS: Metamorphopsia associated with acute BRVO was quantified using M-CHARTS. Initial microstructural changes in the outer retina from acute BRVO may primarily account for the metamorphopsia.

Prevalence, characteristics, and pathogenesis of paravascular inner retinal defects associated with epiretinal membranes.

PURPOSE: To investigate the prevalence, detailed characteristics, and pathogenesis of paravascular inner retinal defects (PIRDs) in eyes with epiretinal membranes (ERMs). METHODS: In this prospective observational case series, we included 81 eyes of 81 patients with idiopathic ERMs, without high myopia. The retinal structure surrounding the PIRDs was assessed using sequential thin sectioning of optical coherence tomography. The PIRDs were classified into three grades. Typical defects of the inner retinal tissue were defined as grade 3. Inner retinal cleavages with openings to the vitreous cavity and no apparent defect of the inner retinal tissue were defined as grade 2. Inner retinal cleavages or cystoid spaces with no connection to the vitreous cavity were defined as grade 1. RESULTS: Of 81 eyes with ERMs, 31 (38.3 %) had PIRDs along the temporal arcade vessels (grade 1 in six eyes, grade 2 in four eyes, and grade 3 in 21 eyes). PIRDs were frequently accompanied by broad defects of the inner retinal tissue (grade 3). Although some ERMs directly adhered to the edge of a PIRD or the retinal vessels, PIRDs were often located outside the area of adhesion to the ERM. In some OCT sections, vitreous traction on the inner retina seemed to contribute to the progression of PIRDs. Visual field abnormalities corresponded to the location of the PIRDs in 44.4 % of eyes with grade 3 PIRDs. CONCLUSIONS: Deviation of retinal vessels due to the traction of the ERMs may contribute to the pathogenesis of PIRDs. PIRDs often cause visual field abnormalities corresponding to the location of the defect.

Pars plana vitrectomy combined with internal limiting membrane peeling for recurrent macular edema due to branch retinal vein occlusion after antivascular endothelial growth factor treatments.

PURPOSE: To evaluate the anatomic and functional outcomes of pars plana vitrectomy combined with internal limiting membrane peeling for recurrent macular edema (ME) due to branch retinal vein occlusion (BRVO) after intravitreal injections of antivascular endothelial growth factor (anti-VEGF) agents. METHODS: Twenty-four eyes of 24 patients with treatment-naive ME from BRVO were treated with intravitreal injections of anti-VEGF agents. Recurred ME was treated with pars plana vitrectomy combined with internal limiting membrane peeling. RESULTS: After the surgery, ME was significantly reduced at 1 month (P=0.031) and the reduction increased with time (P=0.007 at the final visit). With the reduction in ME, treated eyes showed a slow improvement in visual acuity (VA). At the final visit, improvement in VA was statistically significant compared with baseline (P=0.048). The initial presence of cystoid spaces, serous retinal detachment, or subretinal hemorrhage under the fovea, as well as retinal perfusion status, showed no association with VA improvement. However, the presence of epiretinal membrane showed a significant association with the visual recovery. Although eyes without epiretinal membrane showed visual improvement (-0.10±0.32 in logarithm of the minimum angle of resolution [logMAR]), eyes with epiretinal membrane showed greater visual improvement (-0.38±0.12 in logMAR, P=0.012). CONCLUSION: For recurrent ME due to BRVO after anti-VEGF treatment, particularly when accompanied by epiretinal membrane, pars plana vitrectomy combined with internal limiting membrane peeling might be a possible treatment option.

Pars Plana Vitrectomy Combined with Internal Limiting Membrane Peeling to Treat Persistent Macular Edema after Anti-Vascular Endothelial Growth Factor Treatment in Cases of Ischemic Central Retinal Vein Occlusion.

OBJECTIVE: To evaluate the efficacy of pars plana vitrectomy (PPV) combined with internal limiting membrane (ILM) peeling in cases of ischemic central retinal vein occlusion (CRVO) where macular edema (ME) persisted after anti-vascular endothelial growth factor (anti-VEGF) treatment. METHODS: Fifteen eyes with ischemic CRVO-related ME were included in the study. Nine were treated with panretinal photocoagulation after initial examination. Anti-VEGF agents were injected intravitreally. Persistent ME was treated with PPV combined with ILM peeling. During surgery, laser photocoagulation was further applied to the non-perfused area. RESULTS: Mean retinal thickness gradually decreased after surgery (p = 0.024 at 6 months), although visual acuity did not improve significantly during the follow-up period (14.7 ± 11.6 months). Neovascular glaucoma subsequently developed in three cases and a trabeculectomy was performed in one case. CONCLUSION: In eyes with ischemic CRVO, PPV combined with ILM peeling contributed to a reduction in persistent ME. However, there was no significant improvement in visual acuity.

Effect of the renin inhibitor aliskiren against retinal ischemia-reperfusion injury.

The purpose of this study was to investigate the effect of the renin inhibitor, aliskiren, on retinal ischemia-reperfusion injury. Retinal ischemia was induced by increasing intraocular pressure to 130 mmHg. At 7 days after ischemia, retinal damage was evaluated by measuring the retinal thickness and the number of retinal ganglion cells. Western blot was used to measure changes in the (pro)renin receptor expression. Retinal mRNA expressions of prorenin, angiotensinogen and angiotensin II type 1 receptor (AT1-R) were measured by real-time polymerase chain reaction. Rats were treated with the renin inhibitor, aliskiren. Although the number of retinal ganglion cells and the inner retinal thickness were significantly decreased at 7 days after ischemia, treatment with aliskiren significantly inhibited retinal ischemic injury. Administration of aliskiren increased mRNA expression of prorenin in the retina at 3 h after the reperfusion. The expression of the (pro)renin receptor was not changed after ischemia-reperfusion injury with or without aliskiren. Although there was an increase in the retinal expression of AT1-R at 3 h after the reperfusion, aliskiren administration suppressed this expression. A renin inhibitor attenuated subsequent ischemic damage in the rat retina via the inhibition of the prorenin-induced angiotensin generation.

Combined 25-gauge vitrectomy and cataract surgery with toric intraocular lens with idiopathic epiretinal membrane.

PURPOSE: To evaluate the stability of axis rotation, astigmatism correction, and improvement in uncorrected distance visual acuity (UDVA) up to 6 months postoperatively using an astigmatism-correcting intraocular lens (IOL) in a 25-gauge transconjunctival sutureless vitrectomy combined with cataract surgery. SETTING: Department of Ophthalmology, Kagawa University Faculty of Medicine, Kagawa, Japan. DESIGN: Prospective nonrandomized interventional study. METHOD: Eyes with a preoperative corneal cylinder of more than 0.75 diopter (D) had a triple procedure for idiopathic epiretinal membrane (ERM) using an Acrysof IQ toric IOL. Outcome measures were the amount of IOL axis rotation up to 3 months postoperatively, UDVA, corrected distance visual acuity, and corneal and refractive astigmatism up to 6 months postoperatively. A comparison was performed between patients with a target postoperative spherical refraction of emmetropia (toric emmetropic group) and patients who previously had a triple procedure for idiopathic ERM using a nontoric IOL (control group). RESULTS: The mean IOL axis rotation from the end of surgery until 3 months postoperatively was 3.67 degrees ± 3.13 (SD). Six months postoperatively, the mean corneal and refractive cylinders were 1.32 ± 0.61 D and 0.51 ± 0.31 D, respectively, showing a significant difference (P<.0001, paired t test). In addition, the mean UDVA was significantly improved 6 months postoperatively in the control and toric emmetropic group (0.57 logMAR versus 0.35 logMAR) (P=.028), although the toric group was more improved than the control group. CONCLUSION: In vitrectomy (triple procedure) for idiopathic ERM with a toric IOL, postoperative IOL axis stability was similar to that reported for cataract surgery alone. Furthermore, the UDVA was better than with implantation of a spherical IOL.

Neuroprotective effects of angiotensin II type 1 receptor (AT1-R) blocker via modulating AT1-R signaling and decreased extracellular glutamate levels.

PURPOSE: To investigate the mechanism of the neuroprotective effects of the angiotensin II type 1 receptor (AT1-R) blocker against retinal ischemia-reperfusion injury in the rat. METHODS: Retinal ischemia was induced by increasing intraocular pressure. Glutamate release from the rat retina and intravitreal PO(2) (partial pressure of oxygen) profiles were monitored during and after ischemia using a microdialysis biosensor and oxygen-sensitive microelectrodes. ELISA was used to measure changes in the expression of AT1-R. Retinal mRNA expressions of p47phox and p67phox were measured by real-time polymerase chain reaction. Reactive oxygen species (ROS) were measured using dihydroethidium. RESULTS: Administration of candesartan, which is an AT1-R blocker (ARB), suppressed ischemia-induced increases in the extracellular glutamate. Candesartan also attenuated the increase in intravitreal PO(2) during reperfusion. AT1-R expression peaked at 12 hours after reperfusion. Although there was an increase in the retinal mRNA expression of p47phox and p64phox at 12 hours after the reperfusion, administration of candesartan suppressed these expressions. The production of ROS that was detected at 12 hours after reperfusion was also suppressed by the administration of candesartan or apocynin. CONCLUSIONS: NADPH oxidase-mediated ROS production increased at 12 hours after reperfusion. Candesartan may protect neurons by decreasing extracellular glutamate immediately after reperfusion and by attenuating oxidative stress via a modulation of the AT1-R signaling that occurs during ischemic insult.

Activation of the aldosterone/mineralocorticoid receptor system and protective effects of mineralocorticoid receptor antagonism in retinal ischemia-reperfusion injury.

The purpose of this project was to investigate the effects of the mineralocorticoid receptor antagonist against retinal ischemia-reperfusion injury and identify the aldosterone/mineralocorticoid receptor (MR) system in the rat retina. Retinal ischemia was induced by increasing intraocular pressure to 130 mmHg. Rats were treated with the angiotensin II type 1 receptor (AT1-R) antagonist (candesartan), MR antagonist (spironolactone), or aldosterone. Retinal damage was evaluated at 7 days after the ischemia by measuring the retinal thickness and the number of retinal ganglion cells. Pretreatment with candesartan, spironolactone, or candesartan and spironolactone significantly inhibited retinal ischemic injury. However, there was no protective effect against retinal ischemia-reperfusion injury provided by the combined aldosterone with candesartan treatment. Additionally, pretreatment with aldosterone alone also did not provide any neuroprotective effects against retinal ischemia-reperfusion injury. When rats were treated via local administration of aldosterone in the absence of ischemia, the number of retinal ganglion cells decreased while the retinal thickness remained unchanged. The present findings demonstrated the existence of a local aldosterone/MR system in the retina. Our results also demonstrated that an MR antagonist can attenuate subsequent ischemic damage in the rat retina.

Deleterious role of anti-high mobility group box 1 monoclonal antibody in retinal ischemia-reperfusion injury.

PURPOSE: To investigate the effect of anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) against ischemia-reperfusion injury in the rat retina. MATERIALS AND METHODS: Retinal ischemia was induced by increasing and then maintaining intraocular pressure at 130 mmHg for 45 min. An intraperitoneal injection of anti-HMGB1 mAb was administered 30 min before ischemia. Retinal damage was evaluated at 7 days after the ischemia. Immunohistochemistry and image analysis were used to measure changes in the levels of reactive oxygen species (ROS) and the localization of anti-HMGB1 mAb. Dark-adapted full-field electroretinography (ERG) was also performed. RESULTS: Pretreatment with anti-HMGB1 mAb significantly enhanced the ischemic injury of the retina. HMGB1 expression increased at 6-12 h after ischemia in the retina. After the ischemia, production of ROS was detected in retinal cells. However, pretreatment with anti-HMGB1 mAb increased the production of ROS. On the seventh postoperative day, the amplitudes of both the ERG a- and b-waves were significantly higher in the vehicle group than in the groups pretreated with anti-HMGB1 mAb. CONCLUSIONS: The current in vivo model of retinal injury demonstrated that anti-HMGB1 mAb plays a large deleterious role in ischemia-reperfusion injury. In order to develop neuroprotective therapeutic strategies for acute retinal ischemic disorders, further studies on anti-HMGB1 mAb function are needed.