Takashi Ueta

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.

Background Comparison of Typical Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Japanese Patients

OBJECTIVE To compare background factors of the 2 most dominant subtypes of exudative age-related macular degeneration (AMD) in the Japanese population: typical AMD and polypoidal choroidal vasculopathy (PCV). DESIGN Cross-sectional comparison. PARTICIPANTS Consecutive patients with typical AMD (n = 89) and PCV (n = 138) for the primary survey. For the secondary survey, the number of participants was extended to include 148 typical AMD and 170 PCV patients. All the patients included in the present study had been followed up at The University of Tokyo Hospital outpatient macular clinic. METHODS Background data on gender; age; body mass index; smoking; alcohol consumption; and histories of hypertension, diabetes mellitus (DM), hyperlipidemia, ischemic heart disease, stroke, intensive light exposure, central serous chorioretinopathy (CSC), cataract surgery, glaucoma, and steroid use were obtained mainly through interview. The interviewers were masked to the subtype diagnosis of AMD. Univariate and multivariate logistic regression analyses were performed to identify differences in the background factors between typical AMD and PCV. In the secondary survey, the association of a history of CSC and PCV was confirmed further, and funduscopic findings of an atrophic retinal pigment epithelial (RPE) tract and focal photocoagulation scars that could indicate a history of CSC were investigated. MAIN OUTCOME MEASURES Frequency and mean of background factors in patients with typical AMD or PCV. RESULTS The 2 groups showed similar backgrounds with the exception of their histories of DM and CSC. A history of DM was more frequent in typical AMD (24.7% vs. 13.0% in the primary survey; P = 0.027), whereas a history of CSC was more prevalent in PCV (3.4% vs. 14.7% in the secondary survey; P = 0.0005). Funduscopic findings of an atrophic RPE tract or focal photocoagulation scars were found more frequently in PCV (0.7% vs. 7.6%; P = 0.002). CONCLUSIONS Background factors of typical AMD and PCV are similar but not identical. A history of DM and CSC are more frequent in typical AMD and PCV, respectively.

Glutathione Peroxidase 4 is Required for Maturation of Photoreceptor Cells

Background: The essentiality of an antioxidant enzyme for the development and maturation of photoreceptor cells has remained unclear. Results: While GPx4-abrogated photoreceptor cells develop and differentiate into rod and cone cells, their outer segments are structurally disorganized and they undergo rapid apoptosis in vivo. Conclusion: GPx4 is essential for the maturation of photoreceptor cells. Significance: A novel role of an antioxidant enzyme for photoreceptor cells is disclosed in this study. Oxidative stress is implicated in the pathologies of photoreceptor cells, and the protective role of antioxidant enzymes for photoreceptor cells have been well understood. However, their essentiality has remained unknown. In this study we generated photoreceptor-specific conditional knock-out (CKO) mice of glutathione peroxidase 4 (GPx4) and showed the critical role of GPx4 for photoreceptor cells. In the wild-type retina the dominant GPx4 expression was in the mitochondria, indicating the mitochondrial variant was the major GPx4 in the retina. In the GPx4-CKO mice, although photoreceptor cells developed and differentiated into rod and cone cells by P12, they rapidly underwent drastic degeneration and completely disappeared by P21. The photoreceptor cell death in the GPx4-CKO mice was associated with the nuclear translocation of apoptosis-inducing factor (AIF) and TUNEL-positive cells. Photoreceptor cells before undergoing apoptosis (P11) exhibited decreased mitochondrial biomass, decreased number of connecting cilia, as well as disorganized structure of outer segments. These findings indicate that GPx4 is a critical antioxidant enzyme for the maturation and survival of photoreceptor cells.

A parallel robot to assist vitreoretinal surgery

PurposeThis paper describes the development and evaluation of a parallel prototype robot for vitreoretinal surgery where physiological hand tremor limits performance.MethodsThe manipulator was specifically designed to meet requirements such as size, precision, and sterilization; this has six-degree-of-freedom parallel architecture and provides positioning accuracy with micrometer resolution within the eye. The manipulator is controlled by an operator with a “master manipulator” consisting of multiple joints.ResultsResults of the in vitro experiments revealed that when compared to the manual procedure, a higher stability and accuracy of tool positioning could be achieved using the prototype robot.ConclusionsThis microsurgical system that we have developed has superior operability as compared to traditional manual procedure and has sufficient potential to be used clinically for vitreoretinal surgery.

Microsurgical robotic system for vitreoretinal surgery

PurposeRobotics may improve vitreoretinal surgery by steadying hand motion, thereby reducing negative outcomes. This study aimed to develop a microsurgical robot for vitreoretinal surgery and to perform clinical procedures using robot-assisted interventions.MethodsA microsurgical system for vitreoretinal surgery was designed to meet specific requirements for the degree of freedom, accuracy, and workspace. The system was intended to provide micrometer accurate manipulation within the eye. The slave manipulator has a tool change mechanism for switching surgical instruments. The slave manipulator is controlled by the surgeon using a master manipulator consisting of multiple joints.ResultsThe robotic system was used to carry out microcannulation experiments on a pig’s eye. A surgeon was able to successfully perform microcannulation.ConclusionsThis microsurgical robotic vitreoretinal surgical system showed superior operability compared with a traditional manual procedure, and it demonstrated sufficient potential to warrant further testing in animal trials to assess its clinical feasibility.

Vitreomacular interface in typical exudative age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE To investigate the association in Japanese between posterior vitreous attachment and the pathologies of typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV), 2 major forms of exudative AMD. DESIGN Retrospective observational case series. PARTICIPANTS A total of 378 eyes from 302 subjects (132 with typical AMD, 126 with PCV, 120 controls) from the University of Tokyo Hospital. METHODS Posterior vitreous detachment (PVD) and vitreomacular adhesion (VMA) were investigated by B-mode ultrasonography and spectral-domain optical coherence tomography (SD-OCT), respectively. The greatest linear dimension (GLD) of initial photodynamic therapy (PDT) in a subset of the patients (n=92) receiving PDT was also investigated. MAIN OUTCOME MEASURES Number of eyes with complete PVD and with VMA. The GLD of initial PDT. RESULTS In typical AMD eyes, the frequency of complete PVD was significantly lower (63 [56.8%] of 111 eyes) than in the controls (52 [70.3%] of 74 eyes, risk ratio [RR] 0.76, P=0.021) and the frequency of VMA tended to be higher (14/115 [12.2%] in typical AMD eyes and 6/86 [7.0%] in the controls, RR 2.15, P=0.099). The frequency of complete PVD [77 [63.1%] of the 122 eyes] and VMA (9/108 [8.3%]) in PCV eyes was the same as the controls (RR 0.91, P=0.415 and RR 1.29, P=0.615). In patients with unilateral exudative AMD, the frequency of complete PVD was lower in typical AMD eyes than in fellow eyes (odds ratio [OR] 0.111, P=0.026) and VMA was observed in 7 (17.5%) and 3 (7.5%) typical AMD and fellow eyes, respectively (OR 2.33, P=0.34), whereas in PCV eyes, the frequency of complete PVD was higher (OR 8.00, P=0.045) and the frequency of VMA was the same as in the fellow eyes (OR 0.80, P=1.00). The GLD of the eyes without complete PVD or with VMA was significantly larger than that in the eyes with complete PVD in typical AMD eyes (P=0.042) and the same as that in the eyes with complete PVD in PCV eyes (P=0.67). CONCLUSIONS There is an association between posterior vitreous attachment and typical AMD. However, this association is not evident in PCV.

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.

Tomographic and angiographic characteristics of eyes with macular focal choroidal excavation.

Purpose: To describe detailed clinical features of eyes with focal choroidal excavation. Methods: Twenty-one eyes of 17 patients with focal choroidal excavation were retrospectively studied. All eyes underwent thorough examination including funduscopy, visual field analysis, fundus autofluorescence imaging, fluorescein angiography, indocyanine green angiography, and B-scan ultrasonography. Results: Patients’ age ranged between 25 years and 70 years. Four patients (24%) were affected bilaterally. Spherical equivalent of refractive error ranged from 0.5 diopters to −10.0 diopters (D). Funduscopic examination showed hypopigmentation (n = 12) and yellowish plaquelike appearances (n = 2). Indocyanine green angiography showed not only filling defects at the excavation (n = 16) but also choroidal vascular hyperpermeability (n = 7) and punctate hyperfluorescent spots (n = 7). Cicatrized subretinal neovascularization was seen in three eyes. The mean follow-up period was 37 months (6–66 months). There was no change in the appearance of excavation. Central serous chorioretinopathy (n = 1) and choroidal neovascularization (n = 1) developed during follow-up. Conclusion: Background factors and ophthalmic findings are similar to those that have been reported previously, including relatively stable findings even after a long observation and the occurrence of central serous chorioretinopathy and choroidal neovascularization. Bilateral cases are not rare in the current cohort, and choroidal vascular hyperpermeability is frequently observed in indocyanine green angiography, suggesting there were choroidal hemodynamic changes around the excavation.

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.

Development of Typical Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Fellow Eyes of Japanese Patients with Exudative Age-related Macular Degeneration

PURPOSE To investigate the development of typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) in fellow eyes of Japanese patients with exudative AMD. DESIGN Retrospective observational consecutive case series. METHODS Two hundred and sixteen Japanese patients were enrolled in this study from the outpatient clinic of the University of Tokyo Hospital. Ninety-one patients had typical AMD and one hundred and twenty-five patients had PCV. The average follow-up period was 33.6 and 25.1 months for typical AMD and PCV patients. RESULTS The cumulative incidence of involvement in fellow eyes with overall exudative AMD, including both typical AMD and PCV, was 3.4% in one year, 9.3% in three years, and 11.3% in five years. It was 3.6%, 7.3%, and 11.2% in typical AMD, and 3.2%, 11.1%, and 11.1% in PCV in one, three, and five years, respectively. Before the development of exudative AMD, patients with typical AMD had a variety of funduscopic findings including retinal pigment epithelium (RPE) atrophy, drusen, drusenoid pigment epithelial detachments (PED), and normal macula. PCV patients, on the other hand, had funduscopic findings of RPE atrophy. Inner choroidal vascular abnormality of vascular network and polypoidal formation was observed in several eyes before the clinical manifestation of exudative changes. CONCLUSIONS Typical AMD and PCV had similar probabilities of involving the fellow eye in unilaterally affected Japanese patients. RPE atrophy was a prevailing finding in fellow eyes of patients who developed PCV. In PCV, choroidal vascular network and polypoidal formation gradually grow before exudative changes.