Atsuya Miki

Intravitreal Bevacizumab to Treat Iris Neovascularization and Neovascular Glaucoma Secondary to Ischemic Retinal Diseases in 41 Consecutive Cases

PURPOSE To evaluate the biologic efficacy of intravitreal bevacizumab (IVB) for iris neovascularization (INV) or neovascular glaucoma (NVG) in patients with ischemic retinal disorders. DESIGN Retrospective, consecutive, interventional case series. PARTICIPANTS Thirty patients (41 eyes) with INV or NVG secondary to ischemic retinal disorders. METHODS Patients received IVB (1 mg) as the initial treatment for INV or NVG and were followed up for at least 6 months. Ophthalmic evaluations included measurement of visual acuity and intraocular pressure (IOP), a complete ophthalmic examination, and fluorescein angiography. Patients were divided into 3 subgroups: INV without elevated IOP (INV group), NVG with an open angle (O-NVG group), and NVG with angle closure (C-NVG group) for outcomes analysis. MAIN OUTCOME MEASURES The controllability of IOP by IVB, incidence of recurrence, and requirement for surgery to treat NVG. RESULTS No significant ocular or systemic adverse events developed during follow-up (range, 6-22 months; mean, 13.3 months). The mean IOP levels were 14.7, 31.2, and 44.9 mmHg at baseline in the INV, O-NVG, and C-NVG groups, respectively. In the INV group (9 eyes), the INV regressed or resolved after 1 injection. Iris neovascularization recurred in 4 eyes by 6 months and stabilized after repeated injections without IOP elevation. In the O-NVG group (17 eyes), rapid neovascular regression with successful IOP normalization (<or=21 mmHg) occurred in 12 eyes (71%) within 1 week after 1 injection. Five (29%) of the 17 eyes required surgery by 6 months despite repeated IVB injections, and a total of 7 eyes (41%) underwent surgery during follow-up. In the C-NVG group (15 eyes), IVB caused INV resolution but failed to lower the IOP. Fourteen (93%) of 15 eyes required surgery by 2 months after initial IVB and achieved IOP stabilization. The mean interval between IVB and surgery was significantly shorter in the C-NVG group than in the O-NVG group (P<0.001). CONCLUSIONS Intravitreal bevacizumab is well tolerated, effectively stabilized INV activity, and controlled IOP in patients with INV alone and early-stage NVG without angle closure. In advanced NVG, IVB cannot control IOP but may be used adjunctively to improve subsequent surgical results. Further evaluation in controlled randomized studies is warranted.

Evaluation of the choroidal thickness using high-penetration optical coherence tomography with long wavelength in highly myopic normal-tension glaucoma.

PURPOSE To evaluate the choroidal thickness by high-penetration optical coherence tomography (OCT) using long wavelength in highly myopic normal-tension glaucoma (NTG). DESIGN Cross-sectional retrospective study. METHODS SETTINGS Institutional. PARTICIPANTS Twelve eyes from 8 patients under 45 years old, diagnosed as NTG without any other ocular diseases, spherical equivalent refractive error between -6 and -12 diopters, and axial length greater than 26.5 mm; and 12 eyes of matched healthy volunteers. INTERVENTION Choroid was imaged with prototype high-penetration OCT and its thickness was measured. MAIN OUTCOME MEASURES Choroidal thickness at the fovea and 5 locations: 2 mm superior, temporal, and inferior to the center of the optic nerve head, and 2 mm superior (superotemporal) and 2 mm inferior (inferotemporal) to the temporal location. RESULTS Overall, the choroidal thickness in the NTG group was approximately 50% that in controls. Mean choroidal thickness in the NTG group was significantly thinner in the control group at the fovea (166 vs 276 μm, P < .001), superior (172 vs 241 μm, P < 0.05), superotemporal (161 vs 244 μm, P < .01), temporal (110 vs 161 μm, P < .01), and inferotemporal (115 vs 159 μm, P < .05) to the optic nerve head. Stepwise analysis disclosed that the foveal choroidal thickness is the most influential factor on the occurrence of NTG (P < .0001, R(2) = 0.4). CONCLUSIONS Choroidal thickness in highly myopic NTG is significantly thinner than in controls, at least in some specific locations. Choroidal thinning is somehow related with highly myopic NTG and may be a useful diagnostic parameter for myopic NTG.

Protective effect of nilvadipine against glutamate neurotoxicity in purified retinal ganglion cells.

We determined the effect of nilvadipine, a dihydropyridine-type calcium channel blocker, in preventing glutamate neurotoxicity in purified retinal ganglion cells (RGCs). RGCs were purified from dissociated rat retinal cells (postnatal days 6-8), using a modified two-step panning method, and cultured in serum-free medium containing neurotrophic factors and forskolin. RGC survival after exposure to glutamate (25 microM) with nilvadipine or other calcium channel blockers was measured by calcein-acetoxymethyl ester staining after 3 days in culture. Changes in the level of intracellular Ca(2+) ([Ca(2+)](i)) were measured with fura-2 fluorescence. Induction of apoptosis was evaluated using the TDT-dUTP terminal nick-end labeling technique. The neurotoxic effects of low doses of glutamate were blocked by a specific alpha-amino-3-dihydro-5-methylisoxazole-4-propionate-kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (20 microM). Simultaneous application of nilvadipine (1-100 nM) with glutamate protected against glutamate neurotoxicity in a dose-dependent manner. Calcium-imaging experiments showed that the glutamate-evoked [Ca(2+)](i) increase was significantly blocked by nilvadipine (P<0.001), but not nifedipine and diltiazem, in about 50% of RGCs. In addition, the application of nilvadipine significantly reduced glutamate-induced apoptosis (P<0.001). These findings suggest that nilvadipine may partly inhibit glutamate-induced apoptotic cell death by blocking calcium influx via voltage-dependent calcium channels in purified RGCs.

Efficacy of intravitreal bevacizumab as adjunctive treatment with pars plana vitrectomy, endolaser photocoagulation, and trabeculectomy for neovascular glaucoma

Neovascular glaucoma (NVG) is a severe form of glaucoma usually associated with ischaemic retinal diseases.1 When NVG progresses with extensive retinal ischaemia, not only trabeculectomy or aqueous drainage implants alone but aggressive surgery with multiple procedures (par plana vitrectomy (PPV), endolaser photocoagulation, and simultaneous trabeculectomy) should be considered.2–4 However, surgical outcomes in patients with NVG are disappointing.2–4 Intraoperative bleeding and postoperative inflammation are major obstacles to obtaining longitudinal surgical success. Bevacizumab (Avastin, Genentech, San Francisco) is a humanised monoclonal antibody against all vascular endothelial growth factor (VEGF) isoforms.5 Bevacizumab, a potent drug that causes rapid regression of iris and retinal neovascularisation, is a powerful adjunct for preventing intraoperative haemorrhage in proliferative diabetic retinopathy.5 6 We report that bevacizumab also can prevent unexpected …

The assessment of the filtering bleb function with anterior segment optical coherence tomography.

PurposeTo assess the usefulness of anterior segment optical coherence tomography (AS-OCT) in evaluating postoperative filtering bleb function. MethodsForty-eight eyes of 39 patients who had earlier undergone trabeculectomy were enrolled. Blebs were imaged with a commercially available AS-OCT system. The correlation between intraocular pressure (IOP) and 4 quantitative parameters, bleb height, bleb wall thickness, and the height and extent of internal cavity, and 2 qualitative parameters, bleb wall reflectivity, and the presence or absence of posterior episcleral fluid, were analyzed. ResultsOf the 39 participants, 25 (64.1%) were males (mean age, 65.3±10.0 y). The height and extent of the internal cavity and the bleb height were not correlated with the IOP. The bleb wall thickness was negatively (P=0.004) correlated with the IOP. The mean IOP in eyes with a low-reflectivity bleb wall was significantly (P=0.001) lower than in eyes with a high-reflectivity wall. The IOP levels were significantly (P=0.008) lower in eyes with posterior episcleral fluid than in eyes without it. ConclusionsAS-OCT is a useful tool to evaluate filtering bleb function. The height and extent of the total bleb and the internal cavity were not correlated with IOP control. A low-reflectivity wall and the presence of episcleral fluid were associated with lower IOP.

Comparison of enhanced depth imaging and high-penetration optical coherence tomography for imaging deep optic nerve head and parapapillary structures

Purpose To evaluate and compare the abilities of enhanced depth imaging (EDI) and high-penetration optical coherence tomography (HP-OCT) to visualize the deep optic nerve head (ONH) and deep parapapillary structures. Methods Horizontal and vertical optic nerve images were obtained using EDI-OCT and HP-OCT, during the same visit, from 24 eyes of 12 patients with glaucoma. Three graders, using a three-point grading system, independently graded the visibility of the deep ONH structures (prelaminar tissue surface, anterior laminar surface, posterior laminar border, and laminar pores) and deep parapapillary structures (intrascleral vessels, cerebrospinal fluid space, and parapapillary choroid). The differences in the visibility scores between the EDI-OCT and the HP-OCT images and among the image locations were analyzed statistically. The agreement in scoring among the graders also was analyzed. Results The visibility of three ONH structures, the anterior laminar surface, posterior laminar border, and laminar pores, was significantly better with EDI-OCT (P = 0.0010, P < 0.0001, and P = 0.0141, respectively). In contrast, the visibility of all parapapillary structures was significantly better with HP-OCT (P < 0.0001, P = 0.0176, and P < 0.0001, respectively). The visibility scores were better in the vertical images compared with the horizontal images and were best in the temporal quadrants. The intergrader agreement was moderate for all parameters examined. Conclusion Both EDI-OCT and HP-OCT are useful for evaluating the deep ONH and parapapillary structures. The visibility scores of the deep ONH structures were better with EDI-OCT, in contrast to the better visibility scores of the deep parapapillary structures with HP-OCT. Both systems should be chosen depending on the target tissue to observe.

Clinical outcomes and changes in aqueous vascular endothelial growth factor levels after intravitreal bevacizumab for iris neovascularization and neovascular glaucoma: a retrospective two-dose comparative study.

PURPOSE To evaluate the clinical outcomes and biologic effects on the aqueous humor concentrations of vascular endothelial growth factor (VEGF) in patients with neovascular glaucoma (NVG) treated with intravitreal bevacizumab (IVB). METHODS Twenty-nine consecutive patients (35 eyes) treated with 1.0- or 0.1-mg injections of IVB for NVG between January and December 2009 were enrolled in this retrospective, interventional pilot study. The visual prognosis and changes in intraocular pressure (IOP) were followed for >6 months after the initial injection. Aqueous humor samples were obtained at the initial IVB injection from all study eyes and 1 week after the first injection in eyes undergoing a second intervention to measure the VEGF concentration. RESULTS The VEGF concentrations in the 35 eyes significantly correlated (r=0.535, P<0.001) with the pretreatment IOP. The mean reductions of the VEGF levels 1 week after IVB did not differ significantly between the 1.0- and 0.1-mg groups (P=0.738). Despite more repeated injections in the 0.1-mg group and additional medical or surgical interventions in both groups, both dosages inhibited the neovascular activity. The ability to control the IOP after IVB did not differ significantly between groups at 1 week (P=0.625) and 6 months (P>0.99). Visual improvements also did not differ significantly between groups during the 6-month follow-up (P=0.437). CONCLUSIONS Aqueous humor levels of VEGF were significantly correlated with the IOP. Low-dose (0.1 mg) IVB was as effective as the currently used higher dose (1.0 mg) for treating NVG within at least 6 months after the initial injection.

Protective Effect of Donepezil on Retinal Ganglion Cells In Vitro and In Vivo

The neuroprotective effect of donepezil, an acetylcholinesterase inhibitor on retinal ganglion cells (RGCs), was examined. The survival of purified RGCs after exposure to glutamate with or without donepezil (10− 7 M to 10− 5 M) was measured after 3 days in culture. In vivo, the neuroprotective effect of donepezil was examined by quantifying the number of viable RGCs 7 days after axotomy in adult rats. In vitro, donepezil dose-dependently reduced RGC death caused by glutamate toxicity. Oral administration of donepezil (10 mg kg−1 day−1) significantly reduced RGC death after axotomy. In conclusion, donepezil exerts a protective effect on RGCs both in vitro and in vivo.

Evaluation of Glaucoma Progression in Large-Scale Clinical Data: The Japanese Archive of Multicentral Databases in Glaucoma (JAMDIG).

PURPOSE To develop a large-scale real clinical database of glaucoma (Japanese Archive of Multicentral Databases in Glaucoma: JAMDIG) and to investigate the effect of treatment. METHODS The study included a total of 1348 eyes of 805 primary open-angle glaucoma patients with 10 visual fields (VFs) measured with 24-2 or 30-2 Humphrey Field Analyzer (HFA) and intraocular pressure (IOP) records in 10 institutes in Japan. Those with 10 reliable VFs were further identified (638 eyes of 417 patients). Mean total deviation (mTD) of the 52 test points in the 24-2 HFA VF was calculated, and the relationship between mTD progression rate and seven variables (age, mTD of baseline VF, average IOP, standard deviation (SD) of IOP, previous argon/selective laser trabeculoplasties (ALT/SLT), previous trabeculectomy, and previous trabeculotomy) was analyzed. RESULTS The mTD in the initial VF was -6.9 ± 6.2 dB and the mTD progression rate was -0.26 ± 0.46 dB/year. Mean IOP during the follow-up period was 13.5 ± 2.2 mm Hg. Age and SD of IOP were related to mTD progression rate. However, in eyes with average IOP below 15 and also 13 mm Hg, only age and baseline VF mTD were related to mTD progression rate. CONCLUSIONS Age and the degree of VF damage were related to future progression. Average IOP was not related to the progression rate; however, fluctuation of IOP was associated with faster progression, although this was not the case when average IOP was below 15 mm Hg.

Ethnic specific association of the CAV1/CAV2 locus with primary open-angle glaucoma.

A single-nucleotide polymorphism (SNP) rs4236601 at the CAV1/CAV2 locus is associated with primary open-angle glaucoma (POAG). Rs4236601 is common in Caucasians but rare in East Asians. Here we conducted a haplotype-tagging SNP analysis followed by replication in a total of 848 POAG cases and 1574 controls drawn from 3 cities in China and 1 city in Japan. Two SNPs, rs4236601 (odds ratio [OR] = 6.25; P = 0.0086) and a tagging-SNP rs3801994 (OR = 1.32; P = 0.042), were associated with POAG in the Hong Kong Chinese cohort after age and gender adjustments. Rs4236601 was associated with POAG also in Shantou (OR = 6.09; P = 0.0037) and Beijing (OR = 3.92; P = 0.030) cohorts after age and gender adjustment, with a pooled-OR of 5.26 (P = 9.0 × 10−6) in Chinese; but it is non-polymorphic in the Osaka cohort. SNP rs3801994 showed a similar trend of effect in the Shantou and Beijing cohorts, with a pooled-OR of 1.23 (P = 0.022) and 1.20 (P = 0.063) in Chinese, prior to and after age and gender adjustment, respectively; but it showed a reverse effect in the Osaka cohort (OR = 0.58; P = 0.033) after the adjustments. We have thus confirmed the association of rs4236601 with POAG in different Chinese cohorts. Also, we found a common SNP rs3801994 of diverse associations with POAG between Chinese and Japanese.