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Background: OCT angiography (OCTA) and laser speckle flowgraphy (LSFG) are novel and noninvasive imaging modalities which could evaluate fundus blood flow quantitatively. However, the role of OCTA and LSFG as diagnostic tools has not been widely investigated. Previous reports indicated that NO, reduced by hyperglycemia, exerts a key role for the autoregulation of retinal blood flow. We designed this study to evaluate the retinal blood flow by OCTA and LSFG in hyperglycemic DM. Method: 10 patients with extreme hyperglycemia at our outpatient clinic (FPG>250mg/dL, or casual PG>350mg/dL, age 58±5, 7 males, HbA1c 11.1±0.5%) and 32 healthy volunteers (age 48±2, 17 males) were included. Vascular density was calculated using OCTA. LSFG measured relative blood velocity (mean blur rate: MBR) in the optic nerve head (ONH). MBR-A (the mean of all area), MBR-V (the vessel mean) and MBR-T (the tissue mean) were analyzed. Result: OCTA revealed no difference between two groups in the vascular density at macula (47.37±1.14% for DM and 47.44±0.67% for NDM) and a tendency of decrease in the diabetic vascular density at ONH (40.14±3.56% for DM and 42.48±1.25% for NDM) without statistical significance. With LSFG, MBR-A and MBR-T did not exhibit significant differences, while MBR-V significantly decreased in DM compared to the healthy (42.85±2.05% for DM, 49.25±1.34% for NDM, p = 0.025). Discussion: Our results demonstrated that vascular hypoperfusion at ONH was associated with extreme hyperglycemia in DM with tendency to decrease in vascular density. It is generally supposed that the retinal blood flow decreases in DM and acute hyperglycemia. In DM actually presented physiological changes in the retina. Besides, there is a report that autoregulation of blood flow in the ONH is disrupted in diabetic rabbits, as well as in healthy ones with uncoupled gap junctions. It is possible that the similar mechanisms are involved in ONH blood flow decrease observed in this study. Disclosure T. Mitsumatsu: None. F. Yagi: None. Y. Kondo: None. A. Anraku: None. S. Okahata: None. K. Sakamoto: None. G. Tomita: None. T. Shiba: Speaker's Bureau; Self; Shionogi & Co., Ltd., Pfizer Inc., Merck Sharp & Dohme Corp., Kowa Company, Ltd., Daiichi Sankyo Company, Limited.

Purpose.We evaluated the association between optic nerve head (ONH) microcirculation and macular ganglion cell complex (mGCC) thickness in patients with untreated normal tension glaucoma (NTG) and a hemifield defect.Methods.The medical records of 47 patients with untreated NTG were retrospectively reviewed. Laser speckle flowgraphy was used to obtain mean blur rate (MBR), a relative measure of blood flow. Average total deviation (TD), mGCC, and the circumpapillary retinal nerve fiber layer (cpRNFL) thickness were also analyzed.Results.All parameters corresponding to the defective hemifield were significantly lower than those corresponding to the normal hemifield. In the defective hemifield, MBR was correlated with TD, mGCC, and cpRNFL thickness. In the normal hemifield, MBR was only correlated with mGCC thickness, and multiple regression analysis showed that mGCC thickness was a significant contributing factor of the MBR.Conclusion.MBR was well correlated with mGCC thickness in eyes with untreated NTG and a hemifield defect. In the normal hemifield, mGCC thickness was a contributing factor of the MBR indicating that ONH circulatory dysfunction may be associated with retinal structural changes in the early stages of glaucoma. A reduction in ONH microcirculation may be an early indicator of the presence and progression of glaucoma.

Background: To evaluate the incidence and cause of iatrogenic retinal breaks (RBs) and postoperative retinal detachment (RD) in cases of idiopathic macular hole (MH) and epiretinal membrane (ERM). Methods: We analyzed 79 eyes with MH and 41 eyes with ERM, the relationship between the incidence of RBs and RD, and the frequency of posterior vitreous detachment (PVD) and lattice degeneration (LD). Results: The incidence of RBs related to the operation was significantly higher in eyes with MH. The frequency of PVD was significantly higher in eyes with ERM. The frequency of LD did not differ between groups. In the MH group, the incidence of RBs related to the operation was high in eyes without PVD, but with LD. We observed four cases of RD in the MH group. Conclusion: The MH group had higher incidence of RBs related to the operation, especially in eyes without PVD or with LD.

To evaluate the efficacy of vitrectomy with internal limiting membrane (ILM) peeling and SF(6) gas tamponade for macular holes without face-down positioning.Twenty-one eyes of 21 consecutive patients undergoing pars plana vitrectomy with indocyanine green-assisted ILM peeling and 20% SF(6) gas tamponade without face-down positioning were included in this study. Biomicroscopy and optical coherence tomography were used to assess macular hole closure. Pre- and postoperative visual acuities (VAs) were compared.Among the 21 eyes, five (23.8%) had stage 2, 11 (52.4%) stage 3, and five (23.8%) stage 4 macular holes. Mean macular hole size was 0.35 disc diameters. The macular holes had been present for an average of 2.3 months. Twenty eyes (95.2%) were phakic, and one (4.8%) was pseudophakic. Nineteen of the 21 holes (90.5%) initially closed. The final closure rate was 100%, and no eyes showed reopening. Preoperative mean VA (logMAR) was 0.65, and mean VA had significantly improved to 0.46 at 1 month and to 0.42 at 3 months after surgery (P0.0001, repeated measures analysis of variance).Vitrectomy with ILM peeling and SF(6) gas tamponade for macular holes without face-down positioning achieved favorable anatomical and functional results.

Results of vitreous surgery alone in patients with diabetic macular edema (Vit group) were compared with results of surgery combined with peeling of the internal limiting membrane (ILM group), and surgery combined with removal of the residual vitreous cortex after its visualization using triamcinolone acetonide (TA) and a postoperative intravitreal TA injection (TA group). Visual acuities after the operation, degree of improvement in visual acuity (VA), and intra- and postoperative complications were evaluated.The study included 141 consecutive patients (168 eyes) who could be followed up for at least 12 months after the operation. The Vit group consisted of 66 eyes, the ILM group of 62 eyes, and the TA group of 40 eyes. Patient background factors, and visual acuities 6 and 12 months after operation were evaluated first, and at the final examination, the degree of improvement in VA, the incidences of intra- and postoperative complications, and the incidence of intraocular pressureor =25 mmHg were studied.Preoperative VA was compared with the 6- and 12-month postoperative VA and the VA at the final examination. The preoperative to 6 months postoperative improvements and those between the 12-month postoperative and final examination did not differ among the three groups. However, the degree of improvement in VA between 6 and 12 months after the operation was significantly smaller in the TA group than in the other two groups. The incidences of intra- and postoperative complications did not differ among the three groups, but the incidence of intraocular pressure/=25 mmHg was slightly higher in the TA group.Surgical results did not differ among the three operative techniques examined in this study.

Purpose. To evaluate the relationships among the optic nerve head (ONH) area, macular ganglion cell complex (mGCC) thickness, circumpapillary retinal nerve fiber layer (cpRNFL) thickness, and visual field defects in patients with primary open angle glaucoma (POAG).Methods. This retrospective study included 90 eyes of 90 patients with POAG. The ONH area, rim area, mGCC thickness, and cpRNFL thickness were measured using optical coherence tomography. Mean deviation (MD) was measured using standard automated perimetry. The relationships among clinical factors including age, refraction, the ONH area, the rim area, the mGCC thickness, the cpRNFL thickness, and MD were evaluated using correlation coefficients and multiple regression analyses.Results. The significant correlation of the ONH area with refraction (r=0.362,P<0.001), the mGCC thickness (r=0.225,P=0.033), and the cpRNFL thickness (r=0.253,P=0.016) was found. Multiple regression analysis showed that the ONH area, rim area, and MD were selected as significant contributing factors to explain the mGCC thickness and cpRNFL thickness. No factor was selected to explain MD.Conclusions. The ONH area, in other words, the disc size itself may affect the mGCC thickness and cpRNFL thickness in POAG patients.Erratum to “Size of the Optic Nerve Head and Its Relationship with the Thickness of the Macular Ganglion Cell Complex and Peripapillary Retinal Nerve Fiber Layer in Patients with Primary Open Angle Glaucoma”

Purpose To evaluate the efficacy of vitrectomy with internal limiting membrane peeling and sulfur hexafluoride gas tamponade without postoperative face-down positioning for macular holes (MHs) when performed by 3 surgeons at 2 centers. Design A retrospective, consecutive, observational case series. Methods Fifty-seven eyes operated on by 1 of 3 surgeons and followed for 12 months after surgery were studied. Exclusion criteria included cases with MH duration longer than 6 months, secondary MH, and clear lenses. The surgical procedure involved cataract extraction and intraocular lens implantation in all phakic eyes before vitrectomy. Internal limiting membrane removal and 20% sulfur hexafluoride gas tamponade without postoperative face-down positioning were performed in all cases. Preoperative factors [age at surgery, sex, symptom duration, visual acuity (VA), MH size, and MH stage], initial and final hole-closure rates and VA at 1, 3, 6, and 12 months after surgery, were evaluated. Results Mean patient age was 65.3 years. Of the 57 eyes, 40 were in women, and 17 were in men. Macular hole (mean size, 0.30 disc diameter) was present for a mean of 2.37 months. Eight eyes had stage 2, 37 had stage 3, and 12 had stage 4 MH. Fifty-four holes (94.7%) initially closed. Final closure rate was 100%. Mean VA significantly improved from 0.65 to 0.41 at 1 month, 0.35 at 3 months, 0.28 at 6 months, and 0.21 at 12 months after surgery. Conclusions Vitrectomy without face-down positioning for MHs produced favorable anatomic and functional results, regardless of which surgeon performed the procedure.

Retinal pigment epithelium (RPE) transplantation might replace cells lost as a consequence of choroidal neovascular membrane excision in patients with age-related macular degeneration (AMD). Autologous transplantation of RPE cells harvested from a peripheral biopsy may overcome problems of immune rejection. To study the feasibility of autologous RPE cell transplantation, the authors examined the attachment of freshly harvested RPE cells from aged donors onto Bruch's membrane explants, debrided to (1) remove or (2) preserve the RPE basement membrane. Human retinal pigment epithelial sheets were harvested from adult donor eyes (N = 12, mean age 79.00 +/- 9.40 years) and, following incubation in collagenase, were mechanically fragmented into microaggregates. Microaggregates (approximately 120 000 cells) were seeded onto the paired explants (7 mm diameter) and incubated for 20 min, 1, 4, or 24 hr at 37 degrees C. The percent coverage of the debrided surface by microaggregates was determined by sampling the center of the explants with scanning electron microscopy. RPE microaggregate attachment to Bruch's membrane was significantly greater at all time points analysed in samples with intact basement membrane versus those with an exposed inner collagenous layer. Coverage of debridements retaining intact RPE basement membrane was 1.83 +/- 1.10% at 20 min, 3.54 +/- 2.14% at 1 hr, and 8.68 +/- 2.63% at 4 hr. Coverage of debridements lacking basement membrane was 0.10 +/- 0.04% at 20 min, 0.39 +/- 0.25% at 1 hr, and 0.63 +/- 0.42% at 4 hr. Based on their morphologic appearance, many cells were dying as early as 1 hr following seeding. To increase surface coverage, the authors seeded four times the above number of cells and incubated the specimens for 1 hr. Coverage on explants lacking RPE basement membrane showed no increase in the number of cells attached to the inner collagenous layer. There was a significant approximately three-fold increase in the number of cells attached in the presence of basement membrane. These results indicate that if RPE cells from aged human donors are used for transplantation, some modification of the Bruch's membrane surface or the cells must be considered for cell attachment and eventual cell survival.

PURPOSE To compare the thicknesses of the macular ganglion cell complex (mGCC), the entire macular retina, and the peripapillary retinal nerve fiber layer (ppRNFL) in the apparently normal visual field of glaucomatous eyes with hemifield defects with thicknesses in normal eyes. In addition, to evaluate the relationship between the structural and retinal sensitivity parameters by standard automated perimetry. METHODS This single institution study included 50 eyes of 50 glaucoma patients with visual field defects restricted to the superior or inferior hemifield, in addition to 25 eyes of 25 normal controls matched for age, sex, and refractive errors. We measured the thickness of the 3 areas of interest using the automatic algorithm of a spectral-domain optical coherence tomography device. We subsequently compared the difference in these values between the defective and normal hemifields. Furthermore, each optical coherence tomography parameter was correlated with the total deviation values of the parameters in the Humphrey visual field corresponding to each hemisphere. RESULTS The thickness of the mGCC in the normal hemifield of the glaucomatous eyes was significantly less than in normal eyes. In contrast, the total thickness of the macular retinas between the glaucomatous and normal eyes showed no significant difference. In addition, the thicknesses of the mGCC and ppRNFL in the normal hemisphere of the glaucomatous eyes were significantly correlated with the total deviation in the visual field parameters of the corresponding area. CONCLUSIONS In addition to ppRNFL thickness, the mGCC thickness could be a structural parameter for detecting preperimetric glaucoma.

Purpose compare the results of vitrectomy with or without arteriovenous (AV) crossing sheathotomy for macular edema associated with branch retinal vein occlusion (BRVO). Design Interventional case series. Methods A retrospective study of 36 eyes with BRVO-associated macular edema. Twenty eyes underwent AV sheathotomy (AS group), and 16 eyes underwent posterior vitreous detachment (PVD group). Best-corrected visual acuity (BCVA), fluorescein angiography (FA), and optical coherence tomography to determine foveal thickness were conducted preoperatively and at 12 months postoperatively. Results The mean postoperative BCVAs were significantly better in both the AS and the PVD group ( P = .008 and P = .001, respectively). Foveal thickness decreased significantly 1 month after surgery in both groups ( P = .002 and P = .007) and continued to decrease up to 12 months. The postoperative mean BCVA and improvement of BCVA and foveal thickness were not significantly different for the two groups at any postoperative period. Postoperative FA showed reperfusion of the occluded vein in 10 eyes in the AS group and 2 eyes in the PVD group, and formation of shunt vessels at the AV crossing site or around the macular region in all of the other eyes of both groups. Conclusions Both AV sheathotomy and simple PVD significantly reduced macular edema associated with BRVO. However, there was no significant difference in the improvement of macular function following either procedure. Postoperative improvement of retinal circulation by either reperfusion of the occluded vein or collateral vessel formation was found. This accounted for functional and morphologic improvements.

The purpose of this study is to investigate the survival and behaviour of retinal pigment epithelium sheets transplanted onto hydraulically debrided Bruch's membrane. Uncultured retinal pigment epithelium sheets obtained from male cats and sandwiched between two gelatin sheets were transplanted onto the tapetal area of female cats after native retinal pigment epithelium was debrided. For controls, the gelatin carrier was transplanted after debridement. Each transplant or control specimen was analyzed histologically and immunohistochemically. Transplanted male retinal pigment epithelial cells were identified by in situ labelling of the cat Y chromosome. Over half of the transplants appeared as retinal pigment epithelium multilayers in the subretinal space. Retinal pigment epithelium pigment dispersion into the subretinal space was seen in most of the transplants, and retinal pigment epithelium pigment infiltration into the neural retina was seen in all 7-day survival transplants. A few condensed darkly stained retinal pigment epithelium nuclei and Terminal Transferase dUTP Nick End Labelling-positive retinal pigment epithelium cells were observed in all transplants. Cellular retinaldehyde-binding protein was present up to day-7 in most transplanted RPE cells. In both transplant and control specimens, the antibody against the Ki-67 nuclear antigen labelled a few retinal pigment epithelium cells at day-3. Terminal Transferase dUTP Nick End Labelling-positive outer nuclear layer nuclei were most frequently observed at day-1 but were much less frequent at day-3 in both transplants and controls. The survival and effectiveness of retinal pigment epithelium sheet transplants appeared similar to the retinal pigment epithelium microaggregates transplants conducted previously in this model.

Yumi Kamura,1 Yukihiro Sato,2 Yuzou Deguchi,3 Fumihiko Yagi31Department of Ophthalmology, Division of Visual Sciences, Nihon University School of Medicine, Tokyo, Japan; 2Department of Diabetes Center, Jichi Medical University, Tochigi, Japan; 3Department of Ophthalmology, Toho University Sakura Medical Center, Chiba, JapanBackground: We classified iatrogenic retinal break formation during 20-gauge pars plana vitrectomy for proliferative diabetic retinopathy into three types according to the mechanism of development, and evaluated the association of each type with postoperative complications. This is the largest series of such patients published to date.Methods: This was a retrospective comparative study of 760 eyes from 609 cases who underwent primary 20-gauge vitrectomy for proliferative diabetic retinopathy and were followed-up for at least 6 months after surgery. Postoperatively, the eyes were classified as having vitreous hemorrhage only (group 1), fibrovascular membrane without traction retinal detachment (group 2), or fibrovascular membrane with traction retinal detachment (group 3).Results: The overall incidence of iatrogenic retinal breaks was 29%. Fibrovascular membrane dissection was associated with retinal break formation in 50 of the eyes in group 3, an incidence which was significantly higher than that in group 2 (P < 0.001). Posterior vitreous detachment creation and peripheral vitreous shaving were associated with retinal break formation in 8% of eyes overall, and oral dialysis occurred in 2%. Postoperatively, vitreous hemorrhage requiring washout, neovascular glaucoma, recurrent retinal detachments, and fibrovascular proliferation at the sclerotomy sites occurred in 4%, 4%, 3%, and 1%, respectively, of all eyes. Outcomes of eyes with these postoperative complications, other than vitreous hemorrhage, were poor. Multiple regression analysis revealed retinal break formation during fibrovascular membrane dissection to be significantly related to postoperative vitreous hemorrhage (P = 0.019), recurrent retinal detachments (P < 0.001), and neovascular glaucoma (P = 0.048). Oral dialysis was also significantly related to postoperative vitreous hemorrhage (P = 0.001).Conclusion: Iatrogenic retinal break formation during fibrovascular membrane dissection was more likely to be the cause of poor outcomes than peripheral retinal breaks or oral dialysis.Keywords: iatrogenic retinal breaks, 20-gauge vitrectomy, proliferative diabetic retinopathy, postoperative complications

PURPOSE. To determine whether transduction with adeno-associated virus encoding green fluorescent protein (AAV-GFP) is useful for labeling transplanted retinal pigment epithelial cells (RPE). METHODS. Transduction was performed by infection of confluent or subconfluent cultured feline RPE or by subretinal injection. Cells transduced in vitro were analyzed to determine label stability over time and label conservation with cell division. RPE transduced in vivo were harvested at 5 weeks for transplantation or immunohistochemical detection. Two cats received subretinal injections of harvested cells and were killed at 3 or 7 days. RESULTS. In vitro transduction of confluent RPE resulted in stable GFP fluorescence for at least 3 months. There was a marked decline in fluorescence after cell division. Nonconfluent transduced cells conserved label after cell division but showed a marked decline in the number of cells, due to cell death. In vivo transduction resulted in a high level of labeling, allowing labeled cells to be harvested and transplanted. Transplanted cells were detected immunohistochemically. Photoreceptor labeling was detected over areas containing a high density of transplanted, labeled RPE derived from cells transduced in vivo. Possible light toxicity to transduced RPE was observed. CONCLUSIONS. AAV-GFP‐labeling of confluent cultured RPE and RPE in situ can be used to identify transplanted RPE, with some reservations. Cell division may cause dilution of the label, and release of cell contents into the subretinal space may cause label transfer to photoreceptors. Exposure to light of transduced cells should be limited. (Invest Ophthalmol Vis Sci. 2003;44:772‐780) DOI:10.1167/iovs.02-0091