Wei-Chi Wu

Effects and Complications of Bevacizumab Use in Patients with Retinopathy of Prematurity: A Multicenter Study in Taiwan

PURPOSE To investigate the effects and complications of the anti-vascular endothelial growth factor agent bevacizumab in the treatment of retinopathy of prematurity (ROP) in Taiwanese patients. DESIGN A multicenter, retrospective case series study. PARTICIPANTS Twenty-seven patients (49 eyes) from 4 medical centers across Taiwan. METHODS This study included patients receiving intravitreal injections of bevacizumab (IVB) (0.625 mg) for the treatment of ROP between 2007 and 2009 at 4 major medical centers in Taiwan. The effects and complications associated with this treatment were analyzed. Patients were followed for at least 6 months after bevacizumab injection. MAIN OUTCOME MEASURES Regression of ROP and the complications associated with the injection of bevacizumab. RESULTS Forty-nine eyes of 27 patients (18 male and 9 female) were included in the study. Mean gestational age and birth weight were 26.0 ± 2.4 weeks and 971.6 ± 589.6 g, respectively. There were 41 eyes (23 patients) with stage 3 ROP, 6 eyes (3 patients) with stage 4A ROP, and 2 eyes (1 patient) with stage 5 ROP. All of the eyes received only a single injection of IVB. The mean injection time was 36.8 ± 2.6 weeks postmenstrual age for eyes with stage 3 ROP. A total of 37 of 41 eyes (90%) with stage 3 ROP regressed after bevacizumab injection only. Four eyes (10%) required additional laser treatment to regress the ROP. Of 6 eyes (3 patients) with stage 4A ROP, 2 eyes (1 patient; 33%) regressed after bevacizumab injection and 4 eyes (67%) regressed after bevacizumab injection and subsequent vitrectomy. The 2 eyes with stage 5 ROP exhibited decreased vascular tortuosity after bevacizumab injection, but the retina failed to reattach after vitrectomy surgeries. Major complications included vitreous or pre-retinal hemorrhage in 4 eyes (8%) and transient vascular sheathing in 2 eyes (4%). CONCLUSIONS Bevacizumab injection seems effective and well tolerated in some cases of ROP, especially in stage 3 ROP. Ocular complications could result from the injection of bevacizumab in pediatric eyes.

An Updated Study of the Use of Bevacizumab in the Treatment of Patients with Prethreshold Retinopathy of Prematurity in Taiwan

PURPOSE To investigate the effectiveness and complications associated with the use of bevacizumab, an anti-vascular endothelial growth factor agent, in the treatment of prethreshold retinopathy of prematurity (ROP). DESIGN A multicenter, retrospective case series. METHODS Data from patients who had received intravitreal bevacizumab (IVB) injections for the treatment of ROP were collected from 4 medical centers in Taiwan. The main outcome measures were the regression of ROP and the complications that were associated with the IVB injections. RESULTS In total, 162 eyes from 85 patients were included in the study. After receiving IVB injections, 143 eyes (88%) exhibited ROP regression. Fourteen eyes (9%) required additional laser treatment for ROP regression after the absence of a positive response to the IVB injections. Three eyes (2%) progressed to stage 4 ROP and required vitrectomies to reattach the retinas. Two eyes (1%) received 1 additional IVB injection to decrease persistent plus disease. All of the eyes (100%) had attached retinas after the various treatments that they received. The major ocular complications that were associated with IVB injections included vitreous or preretinal hemorrhage in 2 eyes (1%); cataract in 1 eye (1%); and exotropia in 1 eye (1%). No notable systemic complications related to the IVB injections were observed. CONCLUSIONS IVB injection seems to be an effective and well-tolerated method of treating prethreshold ROP. Laser therapy may still be required as a backup treatment for patients who do not respond to an IVB injection or for those in whom ROP worsens after an IVB injection.

Visual Acuity, Optical Components, and Macular Abnormalities in Patients with a History of Retinopathy of Prematurity

PURPOSE To examine the optical components and spectral-domain optical coherence tomography (OCT) findings in children with a history of retinopathy of prematurity (ROP) and to identify any associations between the OCT findings and the visual acuities of the patients. DESIGN Prospective, case-controlled study. PARTICIPANTS AND CONTROLS Children who were between 6 and 14 years of age were divided into the following 4 groups: Patients with a history of threshold ROP who had been treated using laser therapy or cryotherapy (group 1), patients with regressed ROP who had not received any treatment (group 2), patients who were born prematurely but who had no history of ROP (group 3), and normal full-term children (group 4). The posterior poles of the eyes of all of the patients seemed to be normal. METHODS Visual acuities, optical components, and macular thicknesses were measured in 4 groups of patients, and comparisons between the groups were made. Macular thicknesses were measured using OCT. MAIN OUTCOME MEASURES Visual acuity (VA), optical components, and OCT findings. RESULTS We enrolled 133 patients in the study. Patients in group 1 had significantly thicker foveas than the other patients, as demonstrated by OCT, and this finding was negatively correlated with gestational age. The incidence of abnormal foveal contours among patients in group 1 was significantly higher than among the rest of the patients. Retention of the inner retinal layers was noted in group 1 patients; however, the structure of the outer retina remained intact. Greater degrees of myopic shift and astigmatism, steeper corneal curvatures, shallower anterior chamber depths, and thicker lenses were noted in previously treated ROP patients. These findings corresponded with poor VA and high refractive errors in group 1 patients. CONCLUSIONS Patients with a history of threshold ROP are more likely to show abnormal foveal development and have a poorer visual prognosis than other patient groups despite a fundus with no macular dragging, disc dragging, or retinal detachment. A steeper corneal curvature, shallower anterior chamber, and greater lens thickness are the main changes in the optical components in these patients.

Treatment of retinal detachment resulting from posterior staphyloma-associated macular hole in highly myopic eyes.

Purpose: To evaluate the surgical outcome of retinal detachment resulting from a posterior staphyloma–associated macular hole in highly myopic eyes. Methods: Fifty-seven consecutive highly myopic eyes with retinal detachment resulting from a posterior staphyloma–associated macular hole diagnosed between January 1993 and June 2003 were retrospectively studied. Anatomical reattachment of the retina and best-corrected visual acuity were measured. Results: Six different operative methods were used to treat this condition with diverse retinal reattachment rates: long-acting gas tamponade only (12.5%); pars plana vitrectomy (PPV) with long-acting gas tamponade (42.8%); PPV with epiretinal membrane (ERM) peeling and long-acting gas tamponade (50.0%); encircling scleral buckling combined with PPV and long-acting gas tamponade (57.1%); encircling scleral buckling combined with PPV, ERM peeling, and long-acting gas tamponade (40.0%); and encircling scleral buckling combined with PPV and silicone oil tamponade (75.0%). Overall, successful retinal reattachment was achieved in 25 (43.9%) of 57 eyes after the first surgery. However, the ultimate success rate of retinal reattachment was 77.2% (44 of 57 eyes) after subsequent surgery. The mean preoperative visual acuity ± SEM (in logarithm of the minimal angle of resolution units) was 2.08 ± 0.55, and the mean postoperative visual acuity ± SEM was significantly increased to 1.87 ± 0.54 at the last follow-up (P = 0.038). The major cause of recurrent retinal detachment in the long-acting gas tamponade group was nonclosure of the macular hole. For vitrectomized eyes, the major cause was reopening of the macular hole, even with ERM formation and proliferative vitreoretinopathy. There was no obvious correlation between the extent of the detachment or lens status and the reattachment rate. Conclusions: The major causes of recurrent retinal detachment in the long-acting gas tamponade and vitrectomized groups were nonclosure of the macular hole and reopening of the macular hole, respectively. Furthermore, a lesser extent of retinal detachment was not associated with a higher anatomical success rate. More aggressive treatment such as silicone oil tamponade may need to be performed to overcome reduced natural adhesion due to posterior staphyloma with marked chorioretinal atrophy. Failure to initiate aggressive treatment can result in an unsatisfactory outcome and repeated surgery.

Choroidal Thickness and Biometric Markers for the Screening of Lacquer Cracks in Patients with High Myopia

Objectives Validation of choroidal thickness and other biometrics measured by spectral domain optical coherence tomography (SD-OCT) in predicting lacquer cracks formation in highly myopic eyes. Methods Patients with a refractive error worse than −8 diopters and moderate myopic maculopathy were recruited into two groups based on the presence or absence of lacquer cracks (36 eyes without and 33 eyes with lacquer cracks). Choroidal thickness, refractive error, and axial length were measured and subjected to receiver operating characteristic curve analysis to identify the optimal cutoff values at predicting lacquer crack formation. The width of the retinal pigment epithelium (RPE), RPE to the inner segment/outer segment line, RPE to the external limiting membrane were also measured and compared to the subfoveal choroidal thickness to assess their relationships as potential markers of lacquer crack formation. Results Lacquer crack is associated with decreased choroidal thickness, lower best-corrected visual acuity, longer axial length and higher refractive errors. Choroidal thickness has the strongest association with lacquer crack formation versus axial length and refractive error. In eyes with lacquer cracks, stellate lacquer cracks are associated with thinner choroidal thickness compared to eyes with linear lacquer cracks. Subfoveal choroidal thickness less than the width of the retinal pigment epithelium to the inner segment/outer segment line is also associated with lacquer crack formation (sensitivity 78.8%, specificity 88.3%, and accuracy 81.2%). Conclusions This study suggests that choroidal thickness and other SD-OCT measurements could be employed clinically to predict the development and severity of lacquer cracks in patients with high myopia.

PLASMIN ENZYME-ASSISTED VITRECTOMY FOR PRIMARY AND REOPERATED EYES WITH STAGE 5 RETINOPATHY OF PREMATURITY

Purpose: To review the surgical outcome of plasmin enzyme-assisted vitreoretinal surgery in managing stage 5 retinopathy of prematurity (ROP). Methods: A retrospective, consecutive interventional cases series of 80 eyes (68 patients) with stage 5 ROP, treated with autologous or maternal plasmin enzyme-assisted vitreoretinal surgery, were reviewed. All study patients underwent surgery between 1995 and 2004 with plasmin enzyme-assisted vitreoretinal surgery. Thirty-eight eyes had previous vitreous surgery without retinal breaks (Group 1). Fifteen eyes had previous vitreous surgery with retinal breaks (Group 2). Twenty eyes received previous laser, and/or cryotherapy, and/or scleral buckling, but no vitrectomy (Group 3). Seven eyes did not receive any treatment previously (Group 4). Results: Postoperative anatomic outcome, functional results, and surgical complications in each group of eyes at an average follow-up of 49 months were recorded. Following surgery of all 80 eyes, anatomic success was achieved in 68.8%. Six eyes (7.5%) achieved 20/60 to 20/600 vision. Fifty-nine eyes (73.8%) achieved vision worse than 20/600 to light perception. Eleven eyes (13.8%) achieved no light perception. Visual results were uncertain in 4 eyes (5%) because of the inability to measure reliably. Conclusion: Plasmin enzyme-assisted vitrectomy in eyes with and without previous vitrectomy surgery can achieve visual improvement in stage 5 ROP. Early intervention with vitreous surgery for stage 4A ROP will achieve better anatomic and visual results and reduce the number of children with stage 5 ROP.

Serum Levels of Vascular Endothelial Growth Factor and Related Factors After Intravitreous Bevacizumab Injection for Retinopathy of Prematurity

IMPORTANCE Intravitreous injections of bevacizumab (IVB) have been found to be effective for the treatment of retinopathy of prematurity (ROP). However, serum levels of vascular endothelial growth factor (VEGF) have been found to be suppressed for 2 weeks after IVB in patients with ROP. Changes in serum VEGF levels after IVB in patients with ROP may be important because VEGF also plays a role in the neurodevelopment of newborns. OBJECTIVE To investigate the correlation of levels of VEGF and related growth factors with bevacizumab levels in the systemic circulation after IVB in patients with type 1 ROP. DESIGN, SETTING, AND PARTICIPANTS We studied a prospective case series at an institutional referral center from December 1, 2011, through February 28, 2013. We enrolled patients with type 1 ROP who received IVB. We collected blood samples before and for as long as 8 weeks after IVB. The samples were tested for serum levels of bevacizumab and growth factors, including VEGF, VEGF receptor 1 (VEGFR1), VEGFR2, Tie2, erythropoietin, transforming growth factor β1, insulinlike growth factor type 1, angiopoietin 1, angiopoietin 2, angiopoietinlike 3, and angiopoietin 4. The serum concentrations of these factors were measured using enzyme-linked immunosorbent assays. MAIN OUTCOMES AND MEASURES Serum levels of VEGF, bevacizumab, and the other growth factors before and for as long as 8 weeks after IVB. RESULTS We enrolled 8 patients with type 1 ROP. Bevacizumab levels were elevated 1 day after IVB in the 3 patients for whom measurements were available (mean [SD], 1425 [1010 (95% CI, 0-3934)] ng/mL; P = .13) and remained detectable in the serum as long as 8 weeks after IVB (285 ng/mL for the 1 patient with a measurement available). Serum VEGF levels were suppressed for the same period (mean [SD] level at 1 day after IVB, 379 [226 (95% CI, 190-568)] pg/mL for the 3 patients with measurements available; at 8 weeks, 216 pg/mL for the 1 patient with a measurement available). We found a negative correlation between the serum levels of bevacizumab and VEGF in the patients with ROP who received IVB (r = -0.43 [95% CI, -0.67 to -0.10]; P = .01). No changes were identified in the serum levels of any of the other factors after IVB. Bevacizumab may interfere with the actual level of VEGF in the serum, and the total VEGF level in the serum cannot be determined when bevacizumab is present. Wide CIs were noted in the measurement of these factors, probably owing to the small number of patients enrolled in this study. CONCLUSIONS AND RELEVANCE Serum VEGF levels were suppressed for 2 months after IVB in patients with type 1 ROP owing to the leakage of bevacizumab into the systemic circulation.

Classification of Early Dry-Type Myopic Maculopathy with Macular Choroidal Thickness

PURPOSE To compare the macular choroidal thickness in 2 types of early dry-type myopic maculopathy. DESIGN Prospective, observational, comparative study. METHODS Patients with a refractive error of less than -8 diopters were included and were classified into 2 groups. Group 1 consisted of 24 eyes with a tessellated fundus, and group 2 consisted of 33 eyes with diffuse chorioretinal atrophy, but not to the extent of patchy chorioretinal atrophy. These 2 groups were compared with regard to their clinical characteristics, refractive error, axial length, macular choroidal thickness, and best-corrected visual acuity (BCVA). Linear regression was used to evaluate the explanatory variables in terms of macular choroidal thickness and BCVA. RESULTS Patients in group 1 were significantly younger and had better BCVA, less myopia, shorter axial length, and less staphyloma than those in group 2. Refractive error, axial length, and BCVA correlated significantly with macular choroidal thickness in group 2. However, no such significant correlations were observed in group 1. Multiple linear regression analysis showed that age and macular choroidal thickness were the variables that associated most strongly with BCVA, whereas neither refractive error nor axial length was a significant predictor of BCVA. In group 2, eyes with lacquer cracks showed worse BCVA and thinner macular choroidal thickness than eyes without lacquer cracks. CONCLUSIONS Macular choroidal thickness is an important factor in myopic maculopathy and can be a better indicator of its severity. These findings suggest that BCVA reduction in eyes with dry-type myopic maculopathy can be related to a thinner macular choroidal thickness and to the development of lacquer cracks.

Plasmin enzyme-assisted vitreoretinal surgery in congenital X-linked retinoschisis: surgical techniques based on a new classification system.

Purpose: To review the surgical outcome of autologous plasmin enzyme–assisted vitreoretinal surgery in managing complications associated with congenital X-linked retinoschisis (CXLRS). Methods: Medical records of 20 patients (22 eyes) with CXLRS complications, treated with autologous plasmin enzyme–assisted vitreoretinal surgery, were reviewed. Surgical techniques were adapted according to a new CXLRS classification. Results: Median age of the cohort was 3.5 years. Indications for surgical intervention included 8 eyes with schisis involving or threatening the macula, 7 eyes with rhegmatogenous retinal detachment, 4 eyes with tractional retinal detachment, 1 eye with vitreous and intraschisis hemorrhage, 1 eye with obstruction of the macula by an overhanging bullous schisis cavity, and 1 eye with macular pucker. Ninety-one percent (20/22) of eyes had retinal attachment postoperatively after an average of 1.3 procedures per eye. Of the eyes in which visual acuity was measured, 53% (8/15) improved, 33% (5/15) had no change, and 13% (2/15) lost vision. Conclusion: Plasmin enzyme–assisted vitreoretinal surgery is a safe and effective method for managing the complications associated with CXLRS. Most patients had improved or stable postoperative visions.

Fate of Embryonic Stem Cell Derivatives Implanted into the Vitreous of a Slow Retinal Degenerative Mouse Model

Stem cell therapy may be used potentially to treat retinal degeneration and restore vision. Since embryonic stem cells (ESCs) can differentiate into almost any cell types, including those found in the eye, they can be transplanted to repair or replace damaged or injured retinal tissue resulting from inherited diseases or traumas. In this investigation, we explored the potential of ESCs and ESC-derived neuroprogenitors to proliferate and integrate into the diseased retinal tissue of rd12 mice. These rd12 mice mimic the slow and progressive retinal degeneration seen in humans. Both ESCs and ESC-derived neuroprogenitors from ESCs survived and proliferated as evidenced from an increase in yellow fluorescent protein fluorescence. Quantification analysis of cryosectioned retinal tissue initially revealed that both ESCs and neuroprogenitors differentiated into cells expressing neural markers. However, ESC proliferation was robust and resulted in the disruption of the retinal structure and the eventual formation of teratomas beyond 6 weeks postimplantation. In contrast, the neuroprogenitors proliferated slowly, but differentiated further and integrated into the retinal layers of the eye. The differentiation of neuroprogenitors represented various retinal cell types, as judged from the expression of cell-specific markers including Nestin, Olig1, and glial fibrillary acidic protein. These results suggest that ESC-derived neuroprogenitors can survive, proliferate, and differentiate when implanted into the eyes of experimental mice and may be used potentially as cell therapy for treating degenerated or damaged retinal tissue.