Hisanori Imai

Comparative Assessment of Photodynamic Therapy for Typical Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy: A Multicenter Study in Hyogo Prefecture, Japan

Purpose: We aimed to evaluate the effects of photodynamic therapy (PDT) on different phenotypes of age-related macular degenerations (AMD): typical AMD (tAMD) and polypoidal choroidal vasculopathy (PCV). Procedures: 246 eyes from 242 patients (tAMD: 139, PCV: 107 eyes) were recruited. Gender, age, best-corrected visual acuity (BCVA) before treatment, greatest linear dimension before treatment, lesion phenotype and PDT frequency were evaluated for predicting the BCVA at 12 months after PDT using stepwise multiple regression analyses. Additionally, 125 eyes with tAMD and 97 eyes with PCV followed up for more than 12 months after the final PDT were compared for the recurrence period. Results: In the stepwise analysis, a younger age, better pretreatment BCVA, lower PDT frequency, lesions with PCV and a smaller pretreatment greatest linear dimension were all significantly beneficial for a better BCVA at 12 months after PDT. PCV showed a significantly lower PDT frequency and greater improvement in the BCVA than tAMD. The recurrence period of PCV was significantly later than that of tAMD. Conclusions: The phenotype of AMD is significantly correlated with its prognosis after PDT. PCV showed a significantly better response to PDT in terms of BCVA improvement and effect durability.

Natural course and funduscopic findings of polypoidal choroidal vasculopathy in a Japanese population over 1 year of follow-up.

Purpose: To evaluate the natural course and possible funduscopic risk factors for polypoidal choroidal vasculopathy in a Japanese population. Methods: The records of 42 eyes from 41 patients (27 men and 14 women) diagnosed as having polypoidal choroidal vasculopathy located in the macula between November 1999 and October 2005 were retrospectively reviewed. The funduscopic findings at the first visit were evaluated. The changes in the best-corrected visual acuity (BCVA) from the baseline to 12 months were analyzed. The lesion types (clustered vs. nonclustered) found on indocyanine green angiography were compared for changes in the BCVA from the initial visit to 12 months. Results: The mean age of the subjects was 73.8 ± 8.0 years. The mean logarithm of the minimum angle of resolution (LogMAR) BCVA was 0.48 ± 4.0 at baseline and deteriorated to 0.75 ± 5.7 after 12 months, which was statistically significant (P = 0.00075). The mean LogMAR BCVA in the patients showing “nonclustered” polypoidal choroidal lesions on indocyanine green angiography was maintained for 12 months, while that of the “clustered” group decreased significantly during the same period (P = 0.0014). Conclusion: Polypoidal choroidal vasculopathy did not show a favorable outcome in terms of the mean BCVA 12 months after the initial visit. The clustered polypoidal choroidal lesions on indocyanine green angiography may be related to poor prognosis of polypoidal choroidal vasculopathy over the natural course.

Nanoliposomal minocycline for ocular drug delivery

UNLABELLED Nanoliposomal technology is a promising drug delivery system that could be employed to improve the pharmacokinetic properties of clearance and distribution in ocular drug delivery to the retina. We developed a nanoscale version of an anionic, cholesterol-fusing liposome that can encapsulate therapeutic levels of minocycline capable of drug delivery. We demonstrate that size extrusion followed by size-exclusion chromatography can form a stable 80-nm liposome that encapsulates minocycline at a concentration of 450 ± 30 μM, which is 2% to 3% of loading material. More importantly, these nontoxic nanoliposomes can then deliver 40% of encapsulated minocycline to the retina after a subconjunctival injection in the STZ model of diabetes. Efficacy of therapeutic drug delivery was assessed via transcriptomic and proteomic biomarker panels. For both the free minocycline and encapsulated minocycline treatments, proinflammatory markers of diabetes were downregulated at both the messenger RNA and protein levels, validating the utility of biomarker panels for the assessment of ocular drug delivery vehicles. FROM THE CLINICAL EDITOR Authors developed a nano-liposome that can encapsulate minocycline for optimized intraocular drug delivery. These nontoxic nanoliposomes delivered 40% of encapsulated minocycline to the retina after a subconjunctival injection in a diabetes model.

MRP4 knockdown enhances migration, suppresses apoptosis, and produces aggregated morphology in human retinal vascular endothelial cells

The multidrug resistance protein (MRP) MRP4/ABCC4 is an ATP-binding cassette transporter that actively effluxes endogenous and xenobiotic substrates out of cells. In the rodent retina, Mrp4 mRNA and protein are exclusively expressed in vascular endothelial cells, but the angiogenic properties of Mrp4 are poorly understood so far. This study aims to explore the angiogenic properties of MRP4 in human retinal microvascular endothelial cells (HRECs) utilizing the RNA interference (RNAi) technique. MRP4 expression was decreased at the mRNA and protein levels after stimulation with exogenous vascular endothelial growth factor in a dose-dependent manner. RNAi-mediated MRP4 knockdown in HRECs do not affect cell proliferation but enhances cell migration. Moreover, cell apoptosis induced by serum starvation was less prominent in MRP4 siRNA-treated HRECs as compared to control siRNA-treated HRECs. In a Matrigel-based tube-formation assay, although MRP4 knockdown did not lead to a significant change in the total tube length, MRP4 siRNA-treated HRECs assembled and aggregated into a massive tube-like structure, which was not observed in control siRNA-treated HRECs. These results suggest that MRP4 is uniquely involved in retinal angiogenesis.

The upregulation of angiogenic gene expression in cultured retinal pigment epithelial cells grown on type I collagen.

Purpose: Increases in matrix proteins, such as type I collagen and fibronectin, are observed with aging in the retinal pigment epithelium (RPE) basement membrane. However, little is known about altered gene expression profiles of RPE associated with increases in matrix proteins. We investigated changes in gene expression profiles of a human RPE cell line (ARPE-19) cultured on type I collagen. Methods: Visually confluent ARPE-19 cells were grown on either Matrigel (M group) or type I collagen (C group) without serum over 3 days. Total RNA was extracted and reverse transcribed. Gene expression profiles in both groups were compared using microarray analyses. Several angiogenic genes including integrin alpha V, integrin alpha 2, integrin beta 1, integrin beta 3, VEGF-A, VEGF-B, and VEGF-C were subjected to quantitative analyses using real-time PCR. Results: Out of 192 genes examined, angiogenesis-related genes (17.7%) and extracellular matrix–related genes (30.2%) were expressed highly (with more than 1.5-fold difference) in the C group when compared with the M group. In real-time PCR analyses, all VEGF and integrin family genes examined were expressed more in the C group than in the M group. Conclusions: Type I collagen likely causes an upregulation in a number of angiogenic gene expression patterns as seen in RPE in vitro experiments.

Different transitions of multifocal electroretinogram recordings between patients with age-related macular degeneration and polypoidal choroidal vasculopathy after photodynamic therapy.

Aim: To compare and evaluate the transitions in retinal function after photodynamic therapy (PDT) between age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) using multifocal electroretinograms (mfERGs). Methods: 10 eyes with choroidal neovascularisation (CNV) secondary to AMD and 11 eyes with CNV secondary to PCV were included in the study. mfERGs were recorded before PDT, and 1 week and 3 months after PDT. mfERG recordings were acquired by a Veris system (V.3.1.3) using a 103 hexagon stimulus. The first-order kernel was used to calculate amplitudes and latencies. Mean amplitudes and latencies from two central rings rated 0–4° of visual angle were analysed and compared with each disease. Results: In AMD, the mean first negative peak (N1) amplitudes tended to decrease, and the mean first positive peak (N1P1) amplitudes reduced to significant levels (p = 0.047) 1 week after PDT. 3 months after PDT, there were no significant differences in the mean N1 and N1P1 amplitudes compared with pre-PDT values. In PCV, there were no significant changes in the mean N1 and N1P1 amplitudes 1 week after treatment. However, 3 months after PDT, mean amplitudes showed significant increases in N1 (p = 0.008) and N1P1 (p = 0.006) amplitudes compared with pre-PDT values. Conclusions: mfERG recording transitions are different between patients with AMD and those with PCV. In patients with AMD, these results may show transient impairments in retinal function 1 week after PDT, but in those with PCV, the efficacy of PDT is superior to the impairment after PDT.

The Expansion of RPE Atrophy after the Inverted ILM Flap Technique for a Chronic Large Macular Hole.

Purpose: To report a case of the expansion of submacular retinal pigment epithelium (RPE) atrophy after using the inverted internal limiting membrane (ILM) flap technique for a persisting, large, stage IV macular hole (MH). Case Report: A 79-year-old woman presented with a chronic large MH that remained open despite pars plana vitrectomy (PPV). The surgery was performed twice for the MH closure 14 years earlier. ILM peeling was not performed during the previous surgeries. The best-corrected visual acuity (BCVA) with the Landolt ring chart was 0.08 at her visit. The minimum MH diameter was 1,240 μm. Inverted ILM flap technique with 20% SF6 gas tamponade was performed for the MH closure. For the inverted ILM flap technique, 25-gauge PPV and ILM staining with indocyanine green were used. The ILM was peeled off for 2 disc diameters around the MH, but the ILM was not removed completely. The ILM was then inverted and covered the MH. Results: One month after surgery, the MH was closed, accompanied by glial cell proliferation spreading from the inverted ILM flap (as reported before). On the other hand, the area of the submacular RPE atrophy, which was already observed 1 week after surgery, gradually increased in size. BCVA improved to 0.3 six months after the surgery. Conclusions: The inverted ILM flap technique may be promising even for persisting large MH which were not closed in previous surgeries, but long-term observation is needed because the detailed behavior of the inverted ILM and the Müller cells after surgery is not yet known.

Impact of Intravitreal Injection of Tissue Plasminogen Activator on Full-Field Electroretinogram in Patients with Macular Oedema Secondary to Retinal Vein Occlusion

Purpose: To evaluate the retinal toxicity of intravitreal tissue plasminogen activator (tPA) injection for branch and central retinal vein occlusion (BRVO and CRVO) using the electroretinogram (ERG). Procedures: Ten BRVO patients and 5 CRVO patients were enrolled. A complete examination including full-field ERG, visual acuity, central retinal thickness (CRT), and evaluation of systemic and ocular complications was performed before and after intravitreal tPA injection. Results: No significant differences were found in the amplitude or implicit time of any ERG component after tPA injection, and no systemic or ocular complication was observed. The improvement of visual acuity was significant at month 3 in the BRVO group (p < 0.05) but not in the CRVO group. CRT significantly decreased over the course of 3 months in both groups (p < 0.01). Conclusion: Intravitreal tPA injection seems to be a safe and effective treatment option for macular oedema caused by retinal vein occlusions.

Scleral buckling for primary rhegmatogenous retinal detachment using noncontact wide-angle viewing system with a cannula-based 25 G chandelier endoilluminator

Purpose The aim of this study is to report the result of scleral buckling (SB) using a combination of a noncontact wide-angle viewing system and a cannula-based 25 G chandelier endoilluminator. Methods Retrospective analyses of the medical records of 79 eyes of 79 patients with primary uncomplicated rhegmatogenous retinal detachments who had underwent SB using a combination of a noncontact wide-angle viewing system and a chandelier endoilluminator were performed. Results There were 50 men and 29 women. The mean ± standard deviation age was 43.7±16.0 years. Their preoperative best-corrected visual acuity (BCVA) was 0.31±0.65 logMAR units. The final BCVA was 0.10±0.31 logMAR units, which was significantly better than the preoperative BCVA (P<0.01). The initial and final anatomical success rates were 92.4% and 100%, respectively. Backward logistic multiple regression analysis revealed no relationship between explanatory variables and the primary anatomic success (P=0.104). Conclusion SB using a combination of a noncontact wide-angle viewing system and a chandelier endoilluminator is a modified new technique and may be a valid option for the management of rhegmatogenous retinal detachments.

Comparison of the Effectiveness and Prognostic Factors of Intravitreal Ranibizumab between Typical Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy over 24 Months of Follow-Up

Purpose: To compare the response to ranibizumab between patients with typical neovascular age-related macular degeneration (tAMD) and those with polypoidal choroidal vasculopathy (PCV), and to determine the predictors for the outcomes. Methods: Fifty-nine eyes from 59 consecutive patients (tAMD: 27 eyes, PCV: 32 eyes) were treated with three monthly ranibizumab injections followed by as-needed retreatment. Best-corrected visual acuity (BCVA) and morphological parameters were evaluated over 24 months of follow-up. Results: The mean BCVA in tAMD and PCV patients was significantly improved at 3 months (-0.22 and -0.09 logMAR units, respectively). The improvement in BCVA was sustained up to 24 months in tAMD (p = 0.01) but not in PCV patients. The significant predictor for good response to ranibizumab in tAMD patients was the improvement of BCVA at 3 months, whereas that in PCV patients was the anatomical resolution at 3 months. Conclusions: Ranibizumab is an effective therapy for tAMD and PCV over 24 months. The predictors for good outcome might be different between tAMD and PCV.