BRILLIANT BLUE G-ASSISTED INTERNAL LIMITING MEMBRANE PEELING FOR MACULAR HOLE: A Systematic Review of Literature and Meta-Analysis.

PURPOSE: To evaluate the effect of internal limiting membrane peeling with brilliant blue G (BBG) for the treatment of macular hole compared with peeling procedures with other dyes or without dye. METHODS: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically reviewed. Outcome measures were the primary closure rate and postoperative best-corrected visual acuity. RESULTS: Nine studies that included 846 eyes were selected. There was no significant difference in preoperative best-corrected visual acuity between the BBG and no BBG (i.e., other dyes or no dye) groups (mean difference -0.02 logMAR [equivalent to 1 Early Treatment Diabetic Retinopathy Study (ETDRS) letter]; 95% confidence interval -0.09 to 0.04 [-2-4.5 ETDRS letters]; P = 0.45). The macular hole closure rate using BBG was not significantly different from that using indocyanine green (odds ratio 1.98; 95% confidence interval 0.71-5.48; P = 0.19). The postoperative best-corrected visual acuity was more favorable with BBG than with indocyanine green (mean difference -0.10 logMAR [5 ETDRS letters]; 95% confidence interval -0.16 to -0.03 [1.5-8 ETDRS letters]; P = 0.004) or with no BBG (mean difference -0.11 [5.5 ETDRS letters]; 95% confidence interval -0.18 to -0.04 [2-9 ETDRS letters]; P = 0.003). CONCLUSION: BBG could contribute to better visual acuity outcome than other dyes for internal limiting membrane peeling in patients with macular hole; however, it does not significantly influence the closure rate.

The extent of stretched lamellar cleavage and visual acuity in macular pseudoholes.

BACKGROUND/AIMS: To evaluate the extent of lamellar cleavage and its association with preoperative and postoperative visual acuity (VA) in macular pseudoholes. METHODS: One eye each of 50 patients with macular pseudohole who underwent vitrectomy was retrospectively investigated. Preoperative macular pseudoholes were evaluated using spectral-domain optical coherence tomography (SD-OCT) images taken radially around the central fovea at 30° intervals. The macular pseudoholes were categorised into stage 1 (no cleavage), stage 2 (localised cleavage with (2b) and without (2a) crossing central fovea) and stage 3 (diffuse cleavage). RESULTS: Among the 50 macular pseudoholes, 14, 13, 9 and 14 were categorised into stages 1, 2a, 2b and 3, respectively. The extent of stretched cleavages was associated with worse baseline VA (p=0.0049 by multiple regression model). After surgery, the stretched lamellar cleavage disappeared in 32 patients out of 36 who were postoperatively examined by SD-OCT. In addition, the extensive cleavage (stage 2b/3) independently predicted larger postoperative VA recovery at 3 months by 0.105 logMAR compared with no/mild cleavage (stage 1/2a, p=0.030 by multiple regression model). CONCLUSIONS: Although advanced cleavage in macular pseudohole is associated with worse VA before surgery, even an advanced pseudohole could show favourable visual recovery after surgery.

SUPPLEMENTAL SCLERAL BUCKLE IN VITRECTOMY FOR THE REPAIR OF RHEGMATOGENOUS RETINAL DETACHMENT: A Systematic Review of Literature and Meta-Analysis.

PURPOSE: To evaluate the effect of supplemental scleral buckle (SB) in pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment. METHODS: MEDLINE, EMBASE, and CENTRAL were searched to identify studies comparing PPV with supplemental SB (PPV + SB) to PPV alone for the repair of rhegmatogenous retinal detachment. The outcome measures were primary and final reattachment rates, and postoperative complications. Odds ratio with 95% confidence interval in random effects for the comparison of outcomes between PPV + SB and PPV alone was calculated. RESULTS: Ten studies consisting of 1,704 patients were included. Meta-analysis showed that the overall primary reattachment rate was significantly higher in PPV + SB than PPV alone (odds ratio, 1.70; 95% confidence interval, 1.21-2.39; P = 0.002). The final reattachment rate was equally high in both groups. Postoperative development of epiretinal membrane was more frequent in PPV + SB than in PPV alone (odds ratio, 1.89; 95% confidence interval, 1.30-2.76; P = 0.001), whereas no significant difference in postoperative development of macular edema, proliferative vitreoretinopathy, or elevation of intraocular pressure was found. CONCLUSION: Supplemental SB increases the primary reattachment rate in PPV for rhegmatogenous retinal detachment, although final reattachment rate was equally high with or without SB.

EFFECT OF INTERNAL LIMITING MEMBRANE PEELING DURING VITRECTOMY FOR DIABETIC MACULAR EDEMA: Systematic Review and Meta-analysis.

PURPOSE: To evaluate the effect of internal limiting membrane (ILM) peeling during vitrectomy for diabetic macular edema. METHODS: MEDLINE, EMBASE, and CENTRAL were systematically reviewed. Eligible studies included randomized or nonrandomized studies that compared surgical outcomes of vitrectomy with or without ILM peeling for diabetic macular edema. The primary and secondary outcome measures were postoperative best-corrected visual acuity and central macular thickness. Meta-analysis on mean differences between vitrectomy with and without ILM peeling was performed using inverse variance method in random effects. RESULTS: Five studies (7 articles) with 741 patients were eligible for analysis. Superiority (95% confidence interval) in postoperative best-corrected visual acuity in ILM peeling group compared with nonpeeling group was 0.04 (-0.05 to 0.13) logMAR (equivalent to 2.0 ETDRS letters, P = 0.37), and superiority in best-corrected visual acuity change in ILM peeling group was 0.04 (-0.02 to 0.09) logMAR (equivalent to 2.0 ETDRS letters, P = 0.16). There was no significant difference in postoperative central macular thickness and central macular thickness reduction between the two groups. CONCLUSION: The visual acuity outcomes using pars plana vitrectomy with ILM peeling versus no ILM peeling were not significantly different. A larger randomized prospective study would be necessary to adequately address the effectiveness of ILM peeling on visual acuity outcomes.

Quantitative assessment of manual and robotic microcannulation for eye surgery using new eye model.

BACKGROUND: Microcannulation, a surgical procedure for the eye that requires drug injection into a 60-90 µm retinal vein, is difficult to perform manually. Robotic assistance has been proposed; however, its effectiveness in comparison to manual operation has not been quantified. METHODS: An eye model has been developed to quantify the performance of manual and robotic microcannulation. The eye model, which is implemented with a force sensor and microchannels, also simulates the mechanical constraints of the instrument's movement. Ten subjects performed microcannulation using the model, with and without robotic assistance. RESULTS: The results showed that the robotic assistance was useful for motion stability when the drug was injected, whereas its positioning accuracy offered no advantage. CONCLUSIONS: An eye model was used to quantitatively assess the robotic microcannulation performance in comparison to manual operation. This approach could be valid for a better evaluation of surgical robotic assistance.

Systemic vascular safety of ranibizumab for age-related macular degeneration: systematic review and meta-analysis of randomized trials.

BACKGROUND: We conducted a meta-analysis of randomized trials of ranibizumab for age-related macular degeneration (AMD) to elucidate systemic vascular risk. CLINICAL RELEVANCE: Although intravitreal vascular endothelial growth factor inhibitors are widely used to treat AMD, whether they produce systemic adverse effects remains uncertain. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials through March 2014 to identify the randomized trials that compared systemic safety among different intensities of ranibizumab treatment for AMD. The outcome measures were the incidence of cerebrovascular accidents (CVAs), myocardial infarctions, nonocular hemorrhages, overall arterial thromboembolic events (ATEs), and all-cause mortality. We calculated the Peto odds ratio (OR) with 95% confidence interval for the comparisons between different intensities of regimens in terms of dose and retreatment frequency. RESULTS: Eleven trials comprising 6596 patients with AMD were included in the meta-analysis. A significant increase was observed in the following comparisons: 0.5 versus 0.3/0.0 mg for CVA (OR, 1.86; 95% CI, 1.05-3.29; P = 0.03), monthly versus pro re nata (PRN)/0.0 mg for CVA (OR, 1.89; 95% CI, 1.06-3.38; P = 0.03), and 0.3/0.5 versus 0.0 mg for nonocular hemorrhage (OR, 1.57; 95% CI, 1.01-2.44; P = 0.04). A nonsignificant increase was observed in the following comparisons: 0.5 versus 0.0 mg for CVA (OR, 2.27; 95% CI, 0.90-5.69; P = 0.08), monthly versus PRN for CVA (OR, 2.04; 95% CI, 0.94-4.45; P = 0.07), 0.5 versus 0.0 mg for nonocular hemorrhage (OR, 1.68; 95% CI, 0.98-2.88; P = 0.06), 0.3 versus 0.0 mg for nonocular hemorrhage (OR, 1.68; 95% CI, 0.95-2.98; P = 0.07), monthly versus PRN/0.0 mg for nonocular hemorrhage (OR, 1.54; 95% CI, 0.98-2.42; P = 0.06), monthly versus PRN for ATE (OR, 1.58; 95% CI, 0.96-2.61; P = 0.07), and monthly versus PRN/0.0 mg for ATE (OR, 1.42; 95% CI, 0.99-2.05; P = 0.06). Among the other analyses, no protective or harmful effects of ranibizumab were observed. CONCLUSIONS: In ranibizumab treatment for patients with AMD, a possible relationship of more intensive treatment to more systemic vascular adverse events was identified, but no relationship with mortality was identified.

Protective role of glutathione peroxidase 4 in laser-induced choroidal neovascularization in mice.

PURPOSE: To evaluate the influence of glutathione peroxidase 4 (GPx4) expression in retinal pigment epithelium (RPE)/choroid tissue using a mouse model of laser-induced choroidal neovascularization (CNV). METHODS: In this study, GPx4+/-, GPx4+/+, and GPx4-overexpressing transgenic mice were created for comparison. The mRNA and protein expression of vascular endothelial growth factor (VEGF)-A in RPE/choroid tissue were evaluated before and after CNV induction by laser. Moreover, we investigated the changes in the VEGF-A mRNA level in RPE/choroid tissue in the CNV model that have not been clearly shown previously. Lipid peroxidation in RPE/choroid tissue was evaluated by immunohistochemistry using antibody against 4-hydroxy-2-nonenal. To investigate the protective role of GPx4, the size of laser-induced CNV was compared on day 7 among the mice expressing different levels of GPx4. RESULTS: In the laser-induced CNV mouse model, laser treatment reduced the VEGF-A mRNA level in RPE/choroid tissue, while it increased the VEGF-A protein level. Evaluation of VEGF-A expression in RPE/choroid tissue of the GPx4+/-, GPx4+/+, and GPx4 transgenic mice revealed that GPx4 increased the VEGF-A protein level under physiological conditions (i.e., without laser treatment), while GPx4 suppressed the increase in the VEGF-A protein level under pathological conditions (i.e., after CNV induction by laser). In addition, GPx4 reduced the CNV size in a dose-dependent manner in vivo. CONCLUSIONS: GPx4 suppresses the increase in the VEGF-A protein level, which occurs during the development of pathological CNV, thus partly explaining the protective effect of GPx4 against CNV.

Occult macular dystrophy with bilateral chronic subfoveal serous retinal detachment associated with a novel RP1L1 mutation (p.S1199P).

PURPOSE: The purpose of this study was to present an atypical case of occult macular dystrophy (OMD) with bilateral chronic subfoveal serous retinal detachment (SRD). METHODS: A 53-year-old man was ophthalmologically evaluated because of decreased visual acuity in both eyes. Genomic DNA was extracted from venous blood samples. Mutational analysis of the retinitis pigmentosa 1-like 1 (RP1L1) gene was performed by Sanger sequencing. RESULTS: Best-corrected visual acuity (BCVA) was 0.1 logMAR in both eyes until the age of 53, after which it gradually declined. Full-field electroretinography (ERG) was unremarkable, while multifocal ERG revealed a reduced central response in both eyes. Optical coherence tomography showed subfoveal SRD in both eyes, and fundus fluorescein angiography yielded unremarkable results. His brother and cousin had similar subjective symptoms. At age 58, his logMAR BCVA was 0.532 (OD) and 0.347 (OS). He was given 23 administrations of intravitreal bevacizumab (IVB; 1.25 mg) in both eyes alternately over a 2-year period and also underwent reduced-fluence photodynamic therapy in both eyes. Two years after the first administration of IVB, a reduction in SRD was obtained, and IVB was therefore discontinued. Three years after the first administration, logMAR BCVA was 0.155 (OD) and 0.523 (OS). Mutational analysis revealed a novel heterozygous missense mutation (p.S1199P). CONCLUSIONS: We describe in detail a case of bilateral chronic subfoveal SRD in an atypical OMD patient carrying a novel heterozygous RP1L1 mutation (p.S1199P). Our results further extend the phenotypic spectrum of RP1L1-associated OMD.

Long-term increase in subfoveal choroidal thickness after surgery for senile cataracts.

PURPOSE: To evaluate the impact of cataract surgery on subfoveal choroidal thickness and central retinal thickness in the elderly. DESIGN: Prospective observational case series. METHODS: This cohort study included 29 eyes of 29 patients with senile cataract, but no previous ocular surgery or other ocular abnormality. All 29 eyes received standard surgery by phacoemulsification and intraocular lens implantation. Subfoveal choroidal thickness and central retinal thickness were measured at baseline and 1, 3, and 6 months postoperatively by spectral-domain optical coherence tomography. Multiple regression analysis was conducted to identify predictors of larger changes in subfoveal choroidal thickness, including sex, age, baseline choroidal thickness, axial length, refractive status before surgery, and duration of surgery. RESULTS: The 29 patients with senile cataract received cataract surgery without complication. Mean subfoveal choroidal thickness was 193.8, 208.9, 210.2, and 209.3 µm at baseline and at postoperative 1, 3, and 6 months, respectively, with a statistically significant increase after surgery (repeated-measures ANOVA; P < .0001). In 20 eyes (69.0%), subfoveal choroidal thickness remained high even 6 months after surgery. Multiple regression analysis revealed that male sex (P = .014) and thicker baseline choroid (P = .0048) predicted larger increases in subfoveal choroidal thickness. In contrast, the tendency of transient increase in central retinal thickness was not statistically significant. CONCLUSION: Most elderly patients with senile cataracts are expected to maintain increased subfoveal choroidal thickness for at least 6 months after cataract surgery.

Design and development of miniature parallel robot for eye surgery.

A five degree-of-freedom (DOF) miniature parallel robot has been developed to precisely and safely remove the thin internal limiting membrane in the eye ground during vitreoretinal surgery. A simulator has been developed to determine the design parameters of this robot. The developed robot's size is 85 mm × 100 mm × 240 mm, and its weight is 770 g. This robot incorporates an emergency instrument retraction function to quickly remove the instrument from the eye in case of sudden intraoperative complications such as bleeding. Experiments were conducted to evaluate the robot's performance in the master-slave configuration, and the results demonstrated that it had a tracing accuracy of 40.0 µm.

Changes in parafoveal retinal thickness and subfoveal choroidal thickness in a patient with dengue fever-associated maculopathy.

BACKGROUND: The time courses of retinal and choroidal thickness changes in dengue fever-associated maculopathy are not known. We measured central macular thickness (CMT), parafoveal retinal thickness (PRT), and subfoveal choroidal thickness (SCT), in one case, employing optical coherence tomography. FINDINGS: The patient was a 43-year-old man diagnosed with dengue fever in Sri Lanka. He became aware of blurred vision bilaterally and visited our department 2 weeks after the onset. He showed reduced visual acuity. The Amsler test revealed a doughnut-shaped relative scotoma. Based on the course of this condition, dengue fever-associated maculopathy was diagnosed. One month later, 20 mg triamcinolone was injected into sub-Tenon space of the left eye. Both eyes showed subsequent improvement. PRT of both eyes increased 1 week after the first visit and decreased thereafter, reaching a plateau 1 month after the first visit. The change in CMT was minimal. SCT changed markedly, with the similar pattern in both eyes, though no particular tendency was noted during the observation period. CONCLUSIONS: Dengue fever-associated maculopathy appears to be closely associated with thickening of the inner layer of the retina, but not with changes in choroidal thickness.

Impact of robotic assistance on precision of vitreoretinal surgical procedures.

PURPOSE: To elucidate the merits of robotic application for vitreoretinal maneuver in comparison to conventional manual performance using an in-vitro eye model constructed for the present study. METHODS: Capability to accurately approach the target on the fundus, to stabilize the manipulator tip just above the fundus, and to perceive the contact of the manipulator tip with the fundus were tested. The accuracies were compared between the robotic and manual control, as well as between ophthalmologists and engineering students. RESULTS: In case of manual control, ophthalmologists were superior to engineering students in all the 3 test procedures. Robotic assistance significantly improved accuracy of all the test procedures performed by engineering students. For the ophthalmologists including a specialist of vitreoretinal surgery, robotic assistance enhanced the accuracy in the stabilization of manipulator tip (from 90.9 µm to 14.9 µm, P = 0.0006) and the perception of contact with the fundus (from 20.0 mN to 7.84 mN, P = 0.046), while robotic assistance did not improve pointing accuracy. CONCLUSIONS: It was confirmed that telerobotic assistance has a potential to significantly improve precision in vitreoretinal procedures in both experienced and inexperienced hands.

Glycerol-enhanced detection of a preferential structure latent in unstructured 1SS-variants of lysozyme.

Four species of 1SS-varinats of lysozyme were almost unstructured in water, judged from their near-UV CD and (1) H-(15) N-HSQC spectra. Some preferential structure might exist in such a disordered state, but the population of molecules in such a conformation must have been too small to be detected by spectroscopic methods. Indeed, our previous study showed that the addition of 30% glycerol induced the unstructured 2SS-variant of lysozyme to form a native-like structure. To extend this method to more disordered proteins, we attempted to detect some preferential structure latent in unstructured 1SS-variants by the glycerol-enhanced detection. Only in one molecular species of the four 1SS-variants, 1SS[6-127] containing a single disulfide bridge of Cys6-Cys127, a preferential structure was found in the presence of 50% glycerol. It was detected by near-UV CD measurements and the H/D exchange method combined with the NMR spectroscopy. The glycerol-induced structure in 1SS[6-127] was not localized only in the vicinity of Cys6-Cys127, and largely protected regions distributed themselves among A-, B-, and C-helices and Ile55 and Leu56. It was similar to the glycerol-induced structure in 2SS[6-127, 64-80] containing two disulfide bridges of Cys6-Cys127 and Cys64-Cys80, although the former was less rigid than the latter. The role of A-helix (residues 4-15) is proposed as an origin of excellent potential of Cys6-Cys127 for inducing a tertiary structure in the α-domain.

NMR and CD analysis of an intermediate state in the thermal unfolding process of mouse lipocalin-type prostaglandin D synthase.

We previously reported that the thermal unfolding of mouse lipocalin-type prostaglandin D synthase (L-PGDS) is a completely reversible process under acidic conditions and follows a three-state pathway, including an intermediate state (I) between native state (N) and unfolded state. In the present study, we investigated the intermediate state of mouse C65A L-PGDS and clarified the local conformational changes in the upper and bottom regions by using NMR and CD spectroscopy. The (1)H-(15)N HSQC measurements revealed that the backbone conformation was disrupted in the upper region of the ß-barrel at 45°C, which is around the T(m) value for the N ↔ I transition, but that the signals of the residues located at the bottom region of L-PGDS remained at 54°C, where the maximum accumulation of the intermediate state was found. (1)H-NMR and CD measurements showed that the T(m) values obtained by monitoring Trp54 at the upper region and Trp43 at the bottom region of the ß-barrel were 41.4 and 47.5°C, respectively, suggesting that the conformational change in the upper region occurred at a lower temperature than that in the bottom region. These findings demonstrate that the backbone conformation of the bottom region is still maintained in the intermediate state.

NMR analysis of a kinetically trapped intermediate of a disulfide-deficient mutant of the starch-binding domain of glucoamylase.

A thermally unfolded disulfide-deficient mutant of the starch-binding domain of glucoamylase refolds into a kinetically trapped metastable intermediate when subjected to a rapid lowering of temperature. We attempted to characterise this intermediate using multidimensional NMR spectroscopy. The (1)H-(15)N heteronuclear single quantum coherence spectrum after a rapid temperature decrease (the spectrum of the intermediate) showed good chemical shift dispersion but was significantly different from that of the native state, suggesting that the intermediate adopts a nonnative but well-structured conformation. Large chemical shift changes for the backbone amide protons between the native and the intermediate states were observed for residues in the ß-sheet consisting of strands 2, 3, 5, 6, and 7 as well as in the C-terminal region. These residues were found to be in close proximity to aromatic residues, suggesting that the chemical shift changes are mainly due to ring current shifts caused by the aromatic residues. The two-dimensional nuclear Overhauser enhancement (NOE) spectroscopy experiments showed that the intermediate contained substantial, native-like NOE connectivities, although there were fewer cross peaks in the spectrum of the intermediate compared with that of the native state. It was also shown that there were native-like interresidue NOEs for residues buried in the protein, whereas many of the NOE cross peaks were lost for the residues involved in a surface-exposed aromatic cluster. These results suggest that, in the intermediate, the aromatic cluster at the surface is structurally less organised, whereas the interior of the protein has relatively rigid, native-like side-chain packing.

Robot-assisted vitreoretinal surgery: development of a prototype and feasibility studies in an animal model.

PURPOSE: To develop a prototype robotic system designed to assist vitreoretinal surgery and to evaluate its accuracy and maneuverability. DESIGN: Experimental study. PARTICIPANTS: This study used harvested porcine eyes. METHODS: After development of a prototype robotic system, pointing accuracy tests of the system were performed on graph paper and in harvested porcine eyes. The average maximal deviation from the aiming point to the actual position of the tip of the instrument was compared between manually conducted procedures and those conducted with robotic assistance. The feasibility of creating posterior vitreous detachment (PVD), retinal vessel sheathotomy (RVS), and retinal vessel microcannulation also were evaluated in porcine eye models, and the success rates of 4 consecutive attempts for each kind of procedure were evaluated. MAIN OUTCOME MEASURES: The average maximum deviation in pointing accuracy tests both on graph paper and in animal eye models was a main outcome measure. The success rate of making PVD, RVS, and retinal vessel microcannulation was the other primary outcome measure. RESULTS: The pointing accuracy was superior with robotic assistance both on graph paper (327.0 microm vs. 32.3 microm) and in animal eye models (140.8 microm vs. 33.5 microm). Creating PVD, RVS, and retinal vessel microcannulation was feasible in 4 of 4 attempts, 4 of 4 attempts, and 2 of 4 attempts, respectively. The 2 failures in microcannulation were considered to be the result of difficulty in visual differentiation between the retinal vessel and retina in harvested porcine eyes. CONCLUSIONS: Improved accuracy and desirable feasibility of a prototype robotic system to assist vitreoretinal surgery were shown in this study. Research for wider implementation of robot-assisted surgery should be continued; there are some hurdles to overcome.