Tae-im Kim

The Effect of Topical Bevacizumab on Corneal Neovascularization

PURPOSE To examine the effect of topical bevacizumab on corneal neovascularization (NV) over a period of 3 months. DESIGN Prospective, nonrandomized, masked observational case series. PARTICIPANTS Ten eyes of 7 patients with corneal NV. METHODS Patients received topical bevacizumab (1.25%) twice daily. Ophthalmic evaluations included visual acuity, slit-lamp examination, and tonometry. MAIN OUTCOME MEASURES Corneal NV and changes in ophthalmic evaluations. RESULTS Decreased corneal NV was noted in 7 of 10 eyes, usually within 1 month of treatment. Epitheliopathy (epithelial defect, epithelial erosion) was observed in 6 of 10 eyes, 1 resulting in corneal thinning. Adverse effects generally appeared during the second month of treatment. CONCLUSIONS Topical application of bevacizumab was effective in reducing corneal NV within the first month. However, by the second month there was an increased risk of adverse effects.

Novel transglutaminase inhibitors reverse the inflammation of allergic conjunctivitis

Steroidal anti-inflammatory drugs induce proteins that inhibit phospholipase A(2) (PLA(2)), including uteroglobin and lipocortin-1 (annexin I). Uteroglobin and lipocortin-1 retain several conserved sequences. Based on these sequences, several nonapeptides (antiflammins) were synthesized. These nonapeptides were shown to have anti-inflammatory effects in vitro and in vivo, possibly by inhibiting PLA(2). Subsequent research showed that PLA(2) is activated by transglutaminase 2 (TGase 2). We hypothesize here that TGase 2 inhibitors may increase the anti-inflammatory efficacy of inhibiting PLA(2) activity. To test this theory, we constructed recombinant peptides containing sequences from pro-elafin (for inhibition of TGase 2), and from lipocortin-1, lipocortin-5, and uteroglobin (for inhibition of PLA(2)). The recombinant peptides, which had dual inhibitory effects on purified TGase 2 and PLA(2), reversed the inflammation of allergic conjunctivitis to ragweed in a guinea pig model. The present work suggests that novel recombinant peptides may be safe and effective agents for the treatment of various inflammatory diseases.

Bilateral comparison of wavefront-guided versus conventional laser in situ keratomileusis with bausch and lomb zyoptix

PURPOSE One aim of corneal refractive surgery is to correct defocus and astigmatism. In the process of correcting lower order aberrations, higher order ocular aberrations increase. To evaluate the effectiveness of wavefront-guided laser in situ keratomileusis (LASIK) in reducing the increase of higher order aberration, we compared aberrational change after LASIK with conventional and wavefront-guided customized ablation. METHODS Our study included 48 eyes of 24 patients. We performed conventional LASIK in one eye (Group 1) and wavefront-guided customized ablation in the other eye (Group 2). Ocular aberration was measured with the Zywave, a type of Shack-Hartmann aberrometer. We then compared low and high order aberrations, contrast sensitivity, visual acuity, corneal topography, and manifest refraction preoperatively and postoperatively at 1 and 3 months. RESULTS Uncorrected visual acuity improved to more than 20/20 in two eyes in the conventional ablation group and in five eyes in the customized ablation group. In the conventional ablation group, Root-mean-square for higher order (RMS(H)) was 0.215 preoperatively, 0.465 (216.3%) at 1 month, and 0.418 (194.4%) at 3 months. In the customized ablation group, RMS(H) was 0.207 preoperatively, 0.380 (183.6%) at 1 month, and 0.371 (179.2%) at 3 months after LASIK. Mesopic contrast sensitivity in the customized ablation group was higher than that in the conventional ablation group, but this change was not statistically significant. CONCLUSIONS Wavefront-guided customized ablation reduced the increase of high order aberrations resulting from LASIK. In terms of visual acuity, patient preference, and mesopic contrast sensitivity, wavefront-guided customized ablation produced slightly-but not statistically significant-better results.

Accuracy of RTVue Optical Coherence Tomography, Pentacam, and Ultrasonic Pachymetry for the Measurement of Central Corneal Thickness

OBJECTIVE To compare the reliability and the agreement in measuring central corneal thickness (CCT) using the following technologies: RTVue Fourier-domain optical coherence tomography (Optovue, Inc., Fremont, CA), Pentacam (Oculus, Inc., Wetzlar, Germany), and ultrasonic pachymetry (USP; Pocket-II; Quantel Medical, Inc., Bozeman, MT). DESIGN Evaluation of diagnostic test. PARTICIPANTS One hundred four eyes of 52 healthy subjects (mean age ± standard deviation, 28.6 ± 4.8 years). METHODS One eye from each subject was assigned randomly for a repeatability test in which a single operator performed 3 successive measurements. The other eye underwent an interoperator reproducibility test by 3 operators. Two centering methods of RTVue and 3 types of CCT from Pentacam were investigated. For USP, 1 drop of topical anesthetic was administered, and measurement was initiated 90 seconds later. Agreement among the instruments was evaluated using Bland-Altman plots. MAIN OUTCOME MEASURES Various types of CCT were compared: central zone average and minimum thickness of RTVue centering on the vertex and the pupil; corneal thickness at the pupil center, apex, and thinnest location from Pentacam; and mean CCT of 5 repeated measurements of USP. The reliability of measurement was assessed using the repeatability or reproducibility coefficient (Rco), the coefficient of variation, and the intraclass correlation coefficient. The limit of agreement was used to analyze concordance. RESULTS The Rco of RTVue was 4 to 5 μm, which was comparable with that of USP and better than that of Pentacam (10-11 μm). The Rco was not dependent on centering methods (RTVue) or types of CCT (Pentacam). The location of minimum thickness found by RTVue was less reliable than that of the Pentacam. The central zone average of RTVue was approximately 7 μm larger than the pupil center or apex thickness of Pentacam and approximately 13 μm larger than the CCT measurement of USP. Those discrepancies could be as high as 20 and 23 μm, respectively. The minimum thickness measured by the RTVue was similar to that of Pentacam. CONCLUSIONS The RTVue is a rapid and reliable noncontact means of measuring CCT; however, the characteristics of CCT measured by RTVue must be understood when comparing the CCT obtained by the Pentacam or USP. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Analysis of Tear Cytokines and Clinical Correlations in Sjögren Syndrome Dry Eye Patients and Non–Sjögren Syndrome Dry Eye Patients

PURPOSE To compare concentrations of tear cytokines in 3 groups composed of Sjögren syndrome (SS) dry eye, non-Sjögren syndrome (non-SS) dry eye, and normal subjects. Correlations between ocular surface parameters and tear cytokines were also investigated. DESIGN Prospective cross-sectional study. METHODS SS dry eye patients (n = 24; 40 eyes) were diagnosed with primary SS according to the criteria set by the American-European Consensus Group. Non-SS dry eye patients (n = 25; 40 eyes) and normal subjects (n = 21; 35 eyes) were also enrolled. Tear concentrations of interleukin (IL)-17, IL-6, IL-10, IL-4, IL-2, interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) were measured by a multiplex immunobead assay. Ocular Surface Disease Index (OSDI), tear film breakup time (TBUT), Schirmer I test, and fluorescein staining scores were obtained from dry eye patients. RESULTS All cytokine levels except for IL-2 were highest in the SS group, followed by non-SS dry eye group and control subjects. Concentrations of IL-17, TNF-α, and IL-6 were significantly different among the 3 groups (IL-17: SS > control P < .001, non-SS > control P = .042, SS > non-SS P < .001; TNF-α: SS > control P = .006, non-SS > control P = .034, SS > non-SS P = .029; IL-6: SS > control P = .002, non-SS > control P = .032, SS > non-SS P = .002). IL-17 was significantly correlated with TBUT (R = -0.22, P = .012) and Schirmer I test (R = -0.36, P = .027) scores in the SS group. IL-6 was significantly correlated only with TBUT (R = -0.38, P = .02) in the non-SS group. CONCLUSIONS Differences in tear cytokine levels and correlation patterns between SS dry eye and non-SS dry eye patients suggest the involvement of different inflammatory processes as causes of dry eye syndrome.

Central Corneal Thickness Measurements in Unoperated Eyes and Eyes After PRK For Myopia Using Pentacam, Orbscan II, and Ultrasonic Pachymetry

PURPOSE To compare central corneal thickness measurements obtained in unoperated eyes and eyes after myopic photorefractive keratectomy (PRK) using a rotating Scheimpflug camera (Pentacam), a scanning slit corneal topography system (Orbscan II), and ultrasonic pachymetry. METHODS Corneal thickness was measured using Pentacam, Orbscan II, and ultrasonic pachymetry in 25 unoperated eyes (unoperated group), 24 eyes 1 to 3 months after myopic PRK (early postoperative PRK group), and 21 eyes 4 months or more after myopic PRK (late postoperative PRK group). RESULTS In the unoperated group, corneal thickness measurements were similar for all three methods (P=.125). In the early postoperative PRK group, Orbscan measurements were thinner than Pentacam and ultrasonic measurements by a mean of 69.4 microm and 63.4 microm (P<.001 and P=.002, respectively). In the late postoperative PRK group, Orbscan measurements were thinner than Pentacam measurements by a mean of 36.0 microm (P=.017). Pentacam and ultrasonic pachymetry measurements were similar for all three groups with a mean difference of approximately 10 microm. CONCLUSIONS Following myopic PRK, Pentacam was comparable to ultrasonic pachymetry in measuring corneal thickness, whereas Orbscan measurements were thinner.

Inhibition of experimental corneal neovascularization by using subconjunctival injection of bevacizumab (Avastin).

Purpose: To evaluate the effect of subconjunctival bevacizumab (Avastin) administration on corneal neovascularization (NV) in rabbits. Methods: NV was induced by placing a suture at the corneal periphery of the right eye of 20 rabbits. Immediately after suturing and again 1 week later, rabbits were divided into 2 groups and administered a subconjunctival injection of normal saline (control) or bevacizumab (Avastin; 5 mg/0.2 mL), respectively. On day 14, digital photographs of the cornea were taken and analyzed to determine the area of the cornea covered by NV. In addition, immunohistochemical analysis was used to determine CD31 and vascular endothelial growth factor (VEGF) expression in corneal tissue. Results: Analysis of digital photographs showed that there was less corneal NV in bevacizumab-treated eyes than in controls (P < 0.001, Mann-Whitney U test). In addition, there was less staining for VEGF and CD31 in corneas from bevacizumab-treated eyes than in control eyes. Subconjunctival bevacizumab injections were not associated with any complications during observation. Conclusions: Subconjunctival bevacizumab administration decreased suture-induced corneal neovascularization in rabbits.

Bevacizumab application delays epithelial healing in rabbit cornea.

PURPOSE Vascular endothelial growth factor (VEGF) is essential for neovascularization, but the use of anti-VEGF therapies to inhibit neovascularization may influence epithelial wound healing. Here, the effects of bevacizumab on corneal epithelial wound healing time in rabbit models, cell proliferation, and expression of integrins in human corneal epithelial and fibroblast cells were evaluated. METHODS To compare epithelial wound healing times, epithelial defect sizes were measured after application of bevacizumab topical eye drops at 0, 0.5, 1.0, 1.5, 2.5, or 5 mg/mL, twice daily, to mechanically debrided epithelia of rabbit corneas. The cellular covering of wounded areas and expression of Ki67 were assessed after scrape injuries in cultures of human corneal epithelial and fibroblast cells. Expression of cell surface integrins and collagens was measured using plates coated with mouse monoclonal antibodies against human adhesion molecules, and relevant mRNA levels were assessed by reverse-transcription-polymerase chain reaction (RT-PCR). RESULTS The application of bevacizumab topical eye drops at 1.0, 1.5, 2.5, or 5 mg/mL delayed rabbit corneal epithelial healing. Cell cultures growing under high concentrations of bevacizumab showed delay in the proliferation of corneal epithelial and fibroblast cells. Surface expression of mRNA encoding integrins and collagens were decreased by 1.5 mg/mL of bevacizumab. CONCLUSIONS Bevacizumab delayed corneal epithelial wound healing and inhibited integrin expression. When bevacizumab is used to reduce the development of new corneal vessels, slight delays in epithelial wound healing are possible and cellular proliferation is to be expected.

Comparison of laser in situ keratomileusis flaps created by 3 femtosecond lasers and a microkeratome

PURPOSE: To evaluate the thickness and side‐cut angle of laser in situ keratomileusis (LASIK) flaps created by 1 of 3 femtosecond lasers or a microkeratome using Fourier‐domain optical coherence tomography (OCT). SETTING: Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea. DESIGN: Comparative case series. METHODS: Flap creation for bilateral LASIK was performed using an IntraLase (femtosecond group 1), VisuMax (femtosecond group 2), or Femto LDV (femtosecond group 3) femtosecond laser or an M2 microkeratome. Flap thickness was determined at 14 points. The side‐cut angle was measured in 4 directions at the margin interface. Measurements were taken 2 months postoperatively using an RTVue Fourier‐domain OCT device and integrated software. RESULTS: Femtosecond group 1 comprised 50 eyes; femtosecond group 2, 40 eyes; femtosecond group 3, 64 eyes; and the microkeratome group, 52 eyes. Eyes in femtosecond groups 1 and 2 had relatively even flap configuration. Flaps in femtosecond group 3 and the microkeratome group had a meniscus shape. Flaps in femtosecond group 1 had the least difference between the mean peripheral and the central flap thickness (P<.001). The greatest flap thickness predictability (measured versus intended thickness) was in femtosecond group 3 (P<.001). Flaps in femtosecond group 1 had a side‐cut angle closest to 90 degrees (P<.001). CONCLUSIONS: Flap morphology differed according to the system used. The 3 femtosecond laser systems appeared to be superior to the microkeratome system generally. The 3 femtosecond laser systems also produced different flap configurations depending on their individual mechanisms. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

Corneal Dystrophy-associated R124H Mutation Disrupts TGFBI Interaction with Periostin and Causes Mislocalization to the Lysosome

The 5q31-linked corneal dystrophies are heterogeneous autosomal-dominant eye disorders pathologically characterized by the progressive accumulation of aggregated proteinaceous deposits in the cornea, which manifests clinically as severe vision impairment. The 5q31-linked corneal dystrophies are commonly caused by mutations in the TGFBI (transforming growth factor-β-induced) gene. However, despite the identification of the culprit gene, the cellular roles of TGFBI and the molecular mechanisms underlying the pathogenesis of corneal dystrophy remain poorly understood. Here we report the identification of periostin, a molecule that is highly related to TGFBI, as a specific TGFBI-binding partner. The association of TGFBI and periostin is mediated by the amino-terminal cysteine-rich EMI domains of TGFBI and periostin. Our results indicate that the endogenous TGFBI and periostin colocalize within the trans-Golgi network and associate prior to secretion. The corneal dystrophy-associated R124H mutation in TGFBI severely impairs interaction with periostin in vivo. In addition, the R124H mutation causes aberrant redistribution of the mutant TGFBI into lysosomes. We also find that the periostin-TGFBI interaction is disrupted in corneal fibroblasts cultured from granular corneal dystrophy type II patients and that periostin accumulates in TGFBI-positive corneal deposits in granular corneal dystrophy type II (also known as Avellino corneal dystrophy). Together, our findings suggest that TGFBI and periostin may play cooperative cellular roles and that periostin may be involved in the pathogenesis of 5q31-linked corneal dystrophies.