Oral Administration of Cilostazol Increases Ocular Blood Flow in Patients with Diabetic Retinopathy.

PURPOSE: To investigate the effect of cilostazol on ocular hemodynamics and to determine whether the administration of cilostazol increases the ocular blood flow in patients with diabetic retinopathy. METHODS: This prospective observational study investigated the effect of orally administered cilostazol on diabetic retinopathy. Before and after administration for 1 week, pulsatile ocular blood flow (POBF) and retrobulbar hemodynamics were measured using a POBF analyzer and transcranial Doppler imaging, respectively. Visual acuity, intraocular pressure, and blood pressure were also evaluated before and after treatment. RESULTS: Twenty-five eyes of 25 patients were included in this study. POBF increased significantly (16.8 ± 4.6 µL/sec vs. 19.6 ± 6.2 µL/sec, p < 0.001) after administration of cilostazol, while no significant change was identified in visual acuity, intraocular pressure, and blood pressure. Mean flow velocity in the ophthalmic artery as measured with transcranial Doppler imaging also increased significantly after medication (23.5 ± 5.6 cm/sec vs. 26.0 ± 6.9 cm/sec, p = 0.001). The change in POBF directly correlated with the change in mean flow velocity (r = 0.419, p = 0.007). CONCLUSIONS: Cilostazol was effective in increasing ocular blood flow in patients with diabetic retinopathy, possibly by modulating retrobulbar circulation.

Association between diabetic foot ulcer and diabetic retinopathy.

PURPOSE: We aimed to investigate the prevalence of diabetic retinopathy (DR) in patients with diabetic foot ulcer (DFU) and elucidate the association between DR and DFU severities and their shared risk factors. METHODS: A retrospective review was conducted on DFU patients who underwent ophthalmic and vascular examinations within 6 months; 100 type 2 diabetic patients with DFU were included. The medical records of 2496 type 2 diabetic patients without DFU served as control data. DR prevalence and severity were assessed in DFU patients. DFU patients were compared with the control group regarding each clinical variable. Additionally, DFU patients were divided into two groups according to DR severity and compared. RESULTS: Out of 100 DFU patients, 90 patients (90%) had DR and 55 (55%) had proliferative DR (PDR). There was no significant association between DR and DFU severities (R = 0.034, p = 0.734). A multivariable analysis comparing type 2 diabetic patients with and without DFUs showed that the presence of DR [OR, 226.12; 95% confidence interval (CI), 58.07-880.49; p < 0.001] and proliferative DR [OR, 306.27; 95% CI, 64.35-1457.80; p < 0.001), higher HbA1c (%, OR, 1.97, 95% CI, 1.46-2.67; p < 0.001), higher serum creatinine (mg/dL, OR, 1.62, 95% CI, 1.06-2.50; p = 0.027), older age (years, OR, 1.12; 95% CI, 1.06-1.17; p < 0.001), higher pulse pressure (mmHg, OR, 1.03; 95% CI, 1.00-1.06; p = 0.025), lower cholesterol (mg/dL, OR, 0.94; 95% CI, 0.92-0.97; p < 0.001), lower BMI (kg/m2, OR, 0.87, 95% CI, 0.75-1.00; p = 0.044) and lower hematocrit (%, OR, 0.80, 95% CI, 0.74-0.87; p < 0.001) were associated with DFUs. In a subgroup analysis of DFU patients, the PDR group had a longer duration of diabetes mellitus, higher serum BUN, and higher serum creatinine than the non-PDR group. In the multivariable analysis, only higher serum creatinine was associated with PDR in DFU patients (OR, 1.37; 95% CI, 1.05-1.78; p = 0.021). CONCLUSIONS: Diabetic retinopathy is prevalent in patients with DFU and about half of DFU patients had PDR. No significant association was found in terms of the severity of these two diabetic complications. To prevent blindness, patients with DFU, and especially those with high serum creatinine, should undergo retinal examinations for timely PDR diagnosis and management.

PREDICTION OF MORPHOLOGIC DETERIORATION IN PATIENTS WITH LAMELLAR MACULAR HOLES.

PURPOSE: To analyze the morphologic evolution of idiopathic lamellar macular holes (LMHs) as determined by spectral domain optical coherence tomography, and evaluate the utility of retinal function assessments through multifocal electroretinography for predicting the likelihood of morphologic deterioration in LMHs. METHODS: Twenty-eight eyes of 28 patients with LMHs were examined by spectral domain optical coherence tomography at the initial visit and after 12 months. Lamellar macular holes were subdivided into morphologic deterioration (DET) and morphologic maintenance (MAI) groups based on the change in central retinal thickness during the follow-up period. Patients with LMHs were also examined by multifocal electroretinography at the initial visit. Multifocal electroretinography amplitudes were compared between DET and MAI groups, and discriminant function was calculated to predict morphologic deterioration in LMH eyes. RESULTS: During the follow-up period, morphologic deterioration was found in 8 (28.6%) of LMH cases. On multifocal electroretinography, amplitudes in the central ring (R1) and first paracentral ring (R2) were significantly lower in the DET than in the MAI group. Discriminant analysis performed on these two variables yielded a discriminant function with 75% of cases classified correctly. CONCLUSION: Multifocal electroretinography is a useful tool for predicting morphologic deterioration of LMHs. Lower multifocal electroretinography amplitudes in R1 and R2 predict an increased risk of subsequent deterioration.

Relationship Between Vertical and Horizontal Aniseikonia Scores and Vertical and Horizontal OCT Images in Idiopathic Epiretinal Membrane.

PURPOSE: The purpose of this study was to identify the relationship between aniseikonia scores in the vertical and horizontal meridians and the foveal microstructure on vertical and horizontal spectral-domain optical coherence tomography (SD-OCT) in patients with idiopathic epiretinal membrane (ERM). METHODS: All patients (n = 65) with unilateral ERM were examined, and the aniseikonia scores in the vertical (VAS) and horizontal (HAS) meridians were determined using the New Aniseikonia Test. Vertical and horizontal images passing through the fovea were obtained by axial SD-OCT in both eyes. The thicknesses of the ganglion cell layer + inner plexiform layer, inner nuclear layer (INL), and outer retinal layer were measured on the SD-OCT images, and color histograms were analyzed using Photoshop software. RESULTS: Of the 65 ERM patients, 81.5% (53 patients) had macropsia. The VAS and HAS were equal in 52.8% (28 patients). Multiple regression analysis revealed significant correlations between the VAS and vertical INL thickness (R = 0.388, P = 0.001) and between the HAS and horizontal INL thickness (R = 0.349, P = 0.001). The difference between VAS and HAS was proportional to the ratio of the vertical INL thickness to horizontal INL thicknesses (R = 0.370, P < 0.001). CONCLUSIONS: Eyes with ERM mostly presented macropsia. The aniseikonia scores in the vertical and horizontal meridians correlate well with INL thickness on the vertical and horizontal directions of SD-OCT images, respectively. Aniseikonia induced by ERM may be related to the INL thickening detected with SD-OCT.

Identification of vinculin as a potential plasma marker for age-related macular degeneration.

PURPOSE: To identify plasma protein biomarkers for age-related macular degeneration (AMD) using a large-scale quantitative proteomic discovery procedure. METHODS: Plasma proteomes from 20 exudative AMD patients and 20 healthy control patients were comparatively profiled by four-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). Proteins existing at statistically different levels were validated by enzyme-linked immunosorbent assay (ELISA) and Western blotting in 233 case-controlled samples. Newly discovered plasma biomarkers were further confirmed using in vivo and in vitro experiments. RESULTS: Out of 320 proteins identified, vinculin, protein S100A9, triosephosphate isomerase, protein S100A8, protein Z-dependent protease inhibitor, C-X-C motif chemokine 7, and tenascin X showed significantly differential expression in AMD patient plasma compared to control plasma. Among these, the area under the curve (AUC) for vinculin was 0.871 for discriminating between exudative AMD and controls (n = 201) and 0.879 for discriminating between AMD and controls (n = 233). A proteogenomic combination model using vinculin and two known risk genotypes in ARMS2 and CFH genes additionally provided excellent discrimination of AMD from controls (AUC = 0.916). The plasma level of vinculin was not associated with any confounding clinical variables, such as age, smoking, and other comorbidities. Additionally, vinculin was strongly expressed in retinal pigment epithelial cells of human eyes, and its expression was elevated when exposed to oxidative stress in vitro. CONCLUSIONS: Vinculin was identified as a potential plasma biomarker for AMD. The early detection of AMD using novel plasma biomarkers with genetic modeling may enable timely treatment and vision preservation in the elderly.

Effect of diabetic macular edema on peripapillary retinal nerve fiber layer thickness profiles.

PURPOSE: To investigate both the effect of diabetic macular edema (DME) on measured peripapillary retinal nerve fiber layer (RNFL) thickness and the effect of intravitreal bevacizumab injection on RNFL thickness using spectral-domain optical coherence tomography (SD-OCT) in patients with diabetic retinopathy. METHODS: We compared the SD-OCT RNFL thickness profiles between eyes with and without DME (DME [n = 42]; without DME [n = 53]) and conducted an interventional study for evaluating the effect of DME on RNFL thickness. Six sectorial and the global RNFL (gRNFL) thicknesses were compared between the two groups. To evaluate the intraindividual effect of DME on RNFL thickness, 1-month follow-up OCT data of 42 eyes that received an intravitreal bevacizumab injection were compared with preinjection data. RESULTS: The six sectorial and gRNFL thicknesses were greater in the DME group than the non-DME group (P < 0.05). The gRNFL thickness significantly correlated with the central foveal thickness (CFT) (R = 0.470, P < 0.001) and total macular volume (R = 0.786, P < 0.001). The 42 eyes that received intravitreal bevacizumab injections showed significant decreases of the CFT (P < 0.001) and gRNFL thickness (P < 0.001) after injection. Additionally, the changes in macular thickness and RNFL thickness were significantly correlated (R = 0.576, P < 0.001). CONCLUSIONS: The RNFL thickness was generally increased in patients with DME, and the increment correlated with the degree of macular edema. While long-lasting DME resulted in RNFL thickening in all sectors, short-term DME resolution mainly influenced the temporal and nasal RNFL thicknesses. Cautious interpretation is recommended for evaluation of glaucoma using RNFL thickness in diabetic patients, especially patients with DME.

Intraocular pharmacokinetics of ranibizumab in vitrectomized versus nonvitrectomized eyes.

PURPOSE: To analyze the intraocular pharmacokinetic properties of intravitreally injected ranibizumab in vitrectomized and nonvitrectomized rabbit eyes. METHODS: A procedure consisting of 25-gauge pars plana vitrectomy without lensectomy and posterior vitreous detachment was performed in 18 rabbit eyes, and 18 nonvitrectomized rabbit eyes served as controls. Ranibizumab (0.25 mg/0.025 mL) was intravitreally injected in all the vitrectomized and nonvitrectomized eyes. The eyes were enucleated at 1 hour or 1, 2, 5, 14, or 30 days after the intravitreal injections and frozen at -80°C. Ranibizumab concentrations in the vitreous, aqueous humor, and retina were determined using indirect enzyme-linked immunosorbent assay. RESULTS: Vitreous clearance of ranibizumab showed a 2-phase elimination. The vitrectomized and nonvitrectomized eyes showed comparable rates of vitreous clearance of ranibizumab. The vitreous half-life of ranibizumab for up to 14 days was 2.51 and 2.75 days in vitrectomized and nonvitrectomized eyes, respectively. Throughout the 30-day period after intravitreal injection, there were no statistically significant differences between the concentrations of ranibizumab in the vitreous, aqueous humor, and retina of vitrectomized eyes and those in nonvitrectomized eyes. Concentrations of ranibizumab in the vitreous peaked 1 hour after injection, with a mean concentration of 118.01 and 91.61 µg/mL in vitrectomized and nonvitrectomized eyes, respectively. The elimination rate constant of intravitreal ranibizumab in 1-phase analyses showed only a 9% increase in vitrectomized eyes compared to nonvitrectomized eyes. CONCLUSIONS: Overall intraocular pharmacokinetic properties of ranibizumab in vitrectomized eyes were similar to those in nonvitrectomized eyes. Our data do not support the use of different dosing regimens of ranibizumab in vitrectomized eyes.

Multiple subretinal fluid blebs after successful retinal detachment surgery: incidence, risk factors, and presumed pathophysiology.

PURPOSE: To investigate the incidence and the clinical factors associated with the occurrence of multiple subretinal fluid (SRF) blebs after successful rhegmatogenous retinal detachment (RD) repair. DESIGN: Retrospective, observational case series. METHODS: We retrospectively investigated the medical records of 185 eyes of 184 patients who had undergone successful RD surgery, either vitrectomy or scleral buckling. Each patient had undergone spectral-domain optical coherence tomography (SDOCT) combined with infrared reflectance (IR) imaging every 3 months postoperatively. We carefully examined postoperative SDOCT and fundus IR images, in an effort to identify any SRF blebs present. RESULTS: Multiple (≥3) SRF blebs were observed in 40 of 185 cases (21.6%). SRF blebs were first detected 1.7 ± 1.8 months postoperatively. In 22 cases that could be fully followed up, SRF blebs were completely absorbed 13.1 ± 6.1 months postoperatively. Multiple logistic regression analysis showed that only young age (<30 years) was significantly associated with the occurrence of multiple SRF blebs (odds ratio, 5.1; 95% confidence interval, 1.5-17.6; P = .010). Serial measurements of SRF bleb size using SDOCT showed that SRF bleb height was greatest at postoperative 2.9 ± 0.9 months, while SRF bleb width tended to decrease gradually over time. The SRF blebs typically spared large retinal vessels. CONCLUSIONS: Multiple SRF blebs are commonly found after successful RD surgery, especially in young patients. The serial morphologic features evaluated in this study indicate that multiple SRF blebs may result from the active reattachment of retinal pigment epithelium and photoreceptors during the resolution of RD.

Clinical and spectral-domain optical coherence tomography findings in patients with focal choroidal excavation.

OBJECTIVE: To describe the clinical and spectral-domain optical coherence tomography (SD-OCT) findings in patients with focal choroidal excavation (FCE). DESIGN: Retrospective case series. PARTICIPANTS: Forty-one eyes of 38 patients with FCE identified in 2 tertiary medical centers in Korea. METHODS: Clinical features, SD-OCT findings, and associated macular disorders of FCE were analyzed and detailed. MAIN OUTCOME MEASURES: Statistical associations among clinical features, including lesion type, size, and choroidal thickness, and frequency of association with central serous chorioretinopathy (CSC), choroidal neovascularization (CNV), and polypoidal choroidal vasculopathy (PCV). RESULTS: Mean patient age was 50.1 years (range, 25-76 years). The mean spherical equivalent of refractive error was -3.7 diopters (range, -10.0 to +1.5 diopters). Three patients (8%) had bilateral lesions, and 1 patient (3%) had 2 distinct lesions in the same eye. The mean FCE width and depth were 757 µm and 107 µm, respectively, with a positive correlation between width and depth (P = 0.003). The mean subfoveal choroidal thickness of FCE eyes was 284 µm, which was not statistically different from that of age-, sex-, and refractive error-matched normal subjects. Choroidal thickness in FCE was less in eyes with hyperreflective choroidal tissue under the excavation that was present in 22 eyes (54%) versus eyes without excavation (128 vs. 190 µm, respectively; P = 0.009). Twelve FCEs (29%) were the nonconforming type, revealing separation between the photoreceptor tips and the retinal pigment epithelium on SD-OCT. Nonconforming FCE was associated with visual symptoms (P < 0.001) and the presence of concurrent CSC (P = 0.001). Ten eyes (24%) were associated with CSC, and 9 eyes (22%) were associated with CNV, including 1 eye with PCV features. One eye with FCE and type 1 CNV developed a new excavation, and the excavated area in 1 eye with PCV enlarged slightly during follow-up. CONCLUSIONS: Focal choroidal excavation is a relatively common entity and frequently associated with choroidal diseases, including CSC, CNV, and PCV. Although FCE is classically thought to be a congenital malformation, acquired FCE forms possibly exist.

Pharmacokinetics of intravitreally injected bevacizumab in vitrectomized eyes.

PURPOSE: To compare the pharmacokinetics (PKs) of intravitreally injected bevacizumab in vitrectomized versus nonvitrectomized control rabbit eyes. METHODS: Twenty-five-gauge pars plana vitrectomy without lensectomy was performed in 17 right rabbit eyes (V) and 18 nonvitrectomized right rabbit eyes served as controls (C). After 1.25 mg/0.05 mL intravitreal bevacizumab (IVB) injections, eyes were enucleated at 1 h, 1, 2, 5, 14, and 30 days after the injection and immediately frozen at -80°C. Bevacizumab concentrations were determined after separation of frozen vitreous and aqueous humor (AH) compartments using indirect enzyme-linked immunosorbent assay. Bevacizumab concentration-time data were analyzed to obtain PK data. RESULTS: Vitreous clearance of IVB consisted of 2 phases, the first fast distribution and second slow elimination phase. Clearance of IVB was accelerated in V eyes only during the first phase and not in the second phase. The vitreous concentration percent ratios between V and C eyes were 94.7% (1 h), 70.5% (1 day), 89.2% (2 days), 94.2% (5 days), 99.2% (14 days), and 79.1% (30 days). Overall vitreous half-lives were 6.99 and 7.06 days for V and C eyes, respectively (1.6-h difference). CONCLUSION: Overall IVB PKs in rabbit eyes after vitrectomy without lensectomy are not substantially different from nonvitrectomized control eyes.

Comparison of systemic adverse events associated with intravitreal anti-VEGF injection: ranibizumab versus bevacizumab.

The aim of this study was to compare the incidence of systemic adverse events in patients treated with intravitreal injections of bevacizumab or ranibizumab, and to evaluate whether compared to ranibizumab administration, bevacizumab constitutes a higher risk for systemic adverse events. A retrospective review was conducted for 916 consecutive patients treated with at least 1 intravitreal injection of bevacizumab or ranibizumab. Cox regression was performed to assess whether a variable had predictive value for occurrence of new systemic adverse events and to account for different follow-up times. A total of 702 patients were analyzed; 503 patients received bevacizumab alone, and 199 patients received ranibizumab alone. Systemic adverse events occurred in 10 of 702 patients (1.4%): 7 in the bevacizumab group (7/503; 1.4%) and 3 in the ranibizumab group (3/199; 1.5%). This difference was not statistically significant (Fisher's exact test, P = 0.573). Cox proportional hazards analysis of 4 models did not reveal a covariate that significantly changed the hazard for systemic adverse events. In conclusion, compared to ranibizumab, bevacizumab may not increase the risk of systemic adverse events in patients receiving intravitreal injections.

Evaluation of changes of macular thickness in diabetic retinopathy after cataract surgery.

PURPOSE: To assess the macular thickness changes after cataract surgery in diabetic patients using optical coherence tomography (OCT). METHODS: We retrospectively reviewed the records of 104 diabetic patients who underwent cataract surgery. We examined the changes of macular thickness using OCT before cataract surgery and 1 week, 1-, 2- and 6-months after surgery. The central subfield mean thickness (CSMT) was used to evaluate macular edema which was defined as an increase of CSMT (ΔCSMT) > 30% from the baseline. The association between prior laser treatment or severity of diabetic retinopathy and macular thickness were also analyzed. RESULTS: Macular edema occurred in 19 eyes (18%) from the diabetic group and 63% of macular edema developed at 1 month after surgery. Thirteen (68%) out of 19 eyes with macular edema showed the resolution of macular edema by 6 months after surgery without treatment. ΔCSMT of eyes without a history of laser treatment was statistically greater compared to eyes with a history of laser treatment in at 1- and 2-months after surgery, but was not different than eyes who had laser treatment at 6-months after surgery. The severity of diabetic retinopathy was not significantly correlated to macular edema, but there was statistical difference when patients who had a history of prior laser treatment were excluded. CONCLUSIONS: The incidence of macular edema after cataract surgery in diabetic patients was 18%. Its peak incidence was at 1 month post surgery and it resolved spontaneously in 68% of patients by 6 months post surgery. Prior laser treatment might prevent postoperative macular edema until 2 months after cataract surgery in diabetic patients. However, macular edema did not affect the severity of diabetic retinopathy.