Duck Jin Hwang

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.

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.

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.

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 (Fishers 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.

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.

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.

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.

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.

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.

Spontaneous resolution of vitreomacular traction syndrome with persistent vitreofoveal adhesion observed on spectral-domain optical coherence tomography.

tions is sufficient to achieve disease resolution in inflammatory CNV does not seem to be confirmed by this report. We suggest that a treatment plan similar to the one commonly used for AMD-related CNV with a course of three initial monthly injections of ranibizumab and subsequent adaptation to anatomical and functional response may be also pertinent for SC-related CNV leading to favorable visual outcome.