Mechanical impact of epiretinal membranes on the retina utilizing finite element analysis.

BACKGROUND AND OBJECTIVE: Epiretinal membrane (ERM) is a transparent membrane that forms on the surface of the neurosensory retina, causing tangential traction on the retinal surface, which may contribute to cell proliferation and contraction. Epiretinal membranes (ERMs) may be asymptomatic in some patients, while in others the membranes can progress, resulting in macular thickening and macular traction, thus distorting and inducing loss of central visual function and metamorphopsia. Currently, treatment options include follow-up or pars plana vitrectomy with an ERM peel, aiming to relieve the macular traction and improve vision and metamorphopsia. No specific criteria exist for predicting which patients might progress and need early surgery to improve and maintain good vision. The decision for surgery is based on the individual's symptoms and the physician's judgment. This study aimed to evaluate the mechanical impact in terms of stress and deformations of the ERM and to qualitatively compare them with the clinical progression of fovea thickening observed through optical coherence tomography (OCT) images. METHODS: Numerical simulation on a three-dimensional geometrical retina and ERM model was applied to isolate factors that can be used to predict its progression and prognosis. OCT images of 14 patients with ERM were used to derive the fovea thickness progression before and after vitrectomy surgery with ERM peeling. RESULTS: The results clearly show that the increase in ERM contractility level increases the developed stress at the fovea, which spreads and advances toward its base. The highest stress level (2.1 kPa) was developed at the highest and asymmetric contractility, producing non-uniform distributed deformations that distort the fovea structure. CONCLUSIONS: These findings imply that high and asymmetric ERM contractility should be evaluated clinically as a factor that might signal the need for early vitrectomy surgery to avoid irreversible visual loss. Moreover, the OCT images revealed that in some cases, the thickness of the fovea indeed remains high, even after ∼12 months postoperatively, which also indicates that the deformation of the fovea in these cases is irreversible.

Outcomes of Combined Phacovitrectomy Without Corneal Suturing.

BACKGROUND: During combined phacovitrectomy, it is common practice to suture the main corneal incision to prevent intraoperative and postoperative wound leak. However, it may be possible to avoid suturing using a self-sealing corneal incision technique as in standard cataract surgery. OBJECTIVES: To evaluate the clinical outcome, safety, and complications of combined phacovitrectomy without preventive suturing. METHODS: This retrospective case series study included consecutive patients who underwent combined phacovitrectomy between January 2018 and June 2019 for mixed indications. Surgeries were performed at a tertiary university hospital. All surgeries were performed by the same two retinal surgeons. Cataract surgery was performed first, followed by insertion of trocars and vitrectomy. Corneal sutures were not planned but were used at the discretion of the surgeon. RESULTS: The cohort included 106 eyes of 102 patients. Suturing of the main corneal incision was deemed necessary in five cases (5%) because of a main incision leak or anterior chamber shallowing during trocar insertion. No other complications related to the absence of prophylactic corneal sutures were encountered during surgery or follow-up. CONCLUSIONS: Preventive corneal suturing may not be necessary in combined phacovitrectomy surgery and can be used in the few cases in which it is indicated during surgery.

Optical coherence tomography angiography patterns of type 1 macular neovascularization in age-related macular degeneration patients.

PURPOSE: To compare morphologic characteristics of type 1 macular neovascularization (MNV) flow pattern in treatment-naïve and previously treated patients with age-related macular degeneration (AMD) as assessed by optical coherence tomography angiography (OCTA). STUDY DESIGN: Cross-sectional study. MATERIALS AND METHODS: Macular OCT angiography images were acquired using RTVue XR Avanti with AngioVue. Distinct morphologic biomarkers and quantifiable features of the neovascular membranes were studied on en-face projection images comparing treatment-naïve and previously treated patients. RESULTS: The study included 68 eyes of 58 patients. Among them, 24 eyes were treatment-naïve, and the remaining eyes had received a mean of 19.6 injections. Immature lesions were more associated with treatment-naïve eyes and hyper-mature lesions were associated with previously treated eyes (p = 0.005). Tangle pattern was associated with treatment-naïve eyes (p = 0.013), whereas mature core vessels and sea fan pattern were associated more with previously treated eyes (p = 0.001 and p = 0.044, respectively). Vascular density of the neovascular membrane was higher in the treatment-naïve group (p = 0.036) and the average MNV area was similar between the 2 groups (p = 0.683). CONCLUSIONS: Based on OCTA, morphologic biomarkers of type 1 MNV might be an indication of previous treatment. The MNV pattern can improve our understanding of its maturation under anti-VEGF treatment and might be valuable to better guide therapeutic decisions and provide more personalized care to patients with AMD.

Visual acuity outcome in patients with subretinal hemorrhage - office procedure vs. surgical treatment.

PURPOSE: To evaluate the effects of intravitreal injection of tissue plasminogen activator (tPA) and gas vs. pars plana vitrectomy (PPV) surgery as first-line treatment for subretinal hemorrhage. METHODS: Retrospective study of 107 adults treated for subretinal hemorrhage at a tertiary hospital during 2008-2019; 51 received injection of tPA and gas and 56 underwent PPV. RESULTS: No between-group differences were found in age and sex, medical history, use of anticoagulants or antiplatelets, history of ocular surgeries, and previous use of intravitreal anti-VEGF. Overall follow-up time was longer in the PPV group (median 4.9 vs 3.28 years, p = 0.005). The hemorrhage was displaced in a similar percentage of patients in the tPA-and-gas group (n = 40, 78.4%) and the PPV group (n = 45, 80.4%) (p = 0.816). Approximately 80% of patients in the tPA-and-gas group were able to forgo PPV surgery. Visual acuity (in LogMAR) was similar in the two groups prior to the diagnosis of subretinal hemorrhage but better in the tPA-and-gas group at the end of follow-up (p < 0.001). CONCLUSION: Injection of gas and tPA can be done immediately following diagnosis of subretinal hemorrhage as an office procedure. Visual acuity outcome is good, with a high rate of blood displacement. About 20% of patients might require additional PPV as secondary intervention.

Postoperative complications of combined phacoemulsification and pars plana vitrectomy in diabetic retinopathy patients.

Purpose: To compare intra- and postoperative complications in combined phacoemulsification and pars plana vitrectomy surgeries performed in patients with non-proliferative diabetic retinopathy (NPDR) vs. proliferative diabetic retinopathy (PDR). Methods: Retrospective, case series of patients with diabetic retinopathy who underwent combined phacovitrectomy surgery between 2008 and 2017. We compared intraoperative complications including posterior capsular rupture and retinal tear, and postoperative complications including corneal edema, macular edema (ME), epiretinal membrane (ERM), neovascular glaucoma and persistent inflammation. Results: A total of 104 eyes of 104 patients were included in this study. Twenty-four eyes (23.1%) were categorized as NPDR and 80 eyes (76.9%) as PDR. The most common indications for surgery in the NPDR group were ERM (67%) and rhegmatogenous retinal detachment (12.5%), while in the PDR group, indications were vitreous hemorrhage (56%) and tractional retinal detachment (19%). The most common intraoperative complication was retinal tear (8% in NPDR and 19% in PDR, p = 0.195) and postoperative complication was ME (29% in NPDR and 26% in PDR, p = 0.778). There were no statistically significant differences in intra- and postoperative complication rates between the NPDR and PDR groups, even after adjusting for confounders; patient age at surgery and indication for surgery. Conclusion: After combined phacovitrectomy in NPDR and PDR patients, new-onset ME was found in about a quarter of eyes in both groups. Intraoperative anti-VEGF or steroid administration, and intense postoperative anti-inflammatory medication and follow-up should be regarded after phacovitrectomy regardless of the DR level.

Ocular Trauma Caused by Confetti Cannons.

BACKGROUND: Eye trauma is an unfortunate and often preventable cause of vision loss. Confetti cannons are common causes of injury. Awareness of ocular hazards of confetti cannons remains low because of limited reports describing ophthalmic injuries following their use. OBJECTIVES: To describe outcomes of ocular trauma caused by confetti cannons and to increase recognition of their ocular risks. METHODS: A retrospective analysis was conducted of eye injuries caused by confetti cannons presenting to a single medical center between 2016 and 2020. Data collected included age, gender, eye injured, ocular damage, visual outcome, and details of surgeries performed. RESULTS: Overall, six consecutive patients (2 males, mean age 19.5 ± 9.74 years) were identified and studied. In all patients only one eye was injured (3 right eyes) during a private celebration, most commonly (n=5) to a bystander while in the vicinity of a cannon operated by someone else. Most common eye injuries included corneal erosion (n=4), traumatic hyphema (n=4), and retinal edema (n=3). Mean initial logMAR visual acuity in the injured eye was 0.73 ± 0.18, improving to 0.25 ± 0.16 at the final visit (P = 0.125). Two patients underwent eye surgery due to their trauma: one to repair globe penetration and another to undergo intravitreal injection of tissue plasminogen activator and C3F8 for submacular hemorrhage, followed 8 months later by intravitreal bevacizumab injection for choroidal neovascularization. CONCLUSIONS: Confetti cannons pose hazards that can cause severe ocular trauma resulting in permanent vision loss. Increasing awareness of device hazards is necessary to prevent eye injuries.

Prognostic Factors for Low Visual Acuity after Cataract Surgery with Vitreous Loss.

PURPOSE: The purpose of this study is to find prognostic factors associated with low visual acuity in patients experiencing vitreous loss during cataract surgery. METHODS: A retrospective, noncomparative, interventional, case study of patients experiencing vitreous loss during cataract surgery. Data collected included demographics, best corrected visual acuity (BCVA), axial length (AL), presence of ocular comorbidity affecting central vision, timing of intraocular lens (IOL) implantation, position of the implanted lens, and the presence of corneal sutures. Low visual outcome was defined as BCVA < 20/40. RESULTS: Overall, 179 patients (60.3% males) with a mean age of 73 ± 12 years and axial length of 23.5 ± 1.3 mm with a mean follow-up of 12 ± 13 months were included. In multivariable logistic regression analysis, low visual outcome was independently associated with persisting postoperative complications (OR 6.25, 95% CI 1.378-30.9), preexisting ocular comorbidities (OR 4.45, 95% CI 1.1-18.00), and secondary intraocular lens (IOL) implant (OR 10.36, 95% CI 1.8-60.00). Conversely, pars plana vitrectomy (PPV) for dislocated fragments of lens material, age > 70 years, gender, axial length, degree of surgeon, corneal suturing, and anterior chamber lens implantation were not found to have significant associations with low visual outcomes (P > 0.05). CONCLUSIONS: Low visual outcome after vitreous loss during cataract surgery was associated with ocular comorbidities, secondary IOL implantation, development of cystoid macular edema, and additional surgical complications.

Orbital Lymphatic-Venous Malformation Accompanied by an Intraocular Vascular Malformation: A Rare Case Study.

Lymphatic-venous malformations (LVMs) are development defects that result in abnormal connections between the lymphatic and venous systems. The authors describe a 7-weeks-old female infant who presented with a right orbital LVM extending to the ipsilateral cheek and subconjunctiva of the right eye, intracranial developmental venous anomalies in the right cerebellum, and a significant right eye intraocular retinal vascular malformation. Since orbital LVM is usually diagnosed in infancy or childhood, pediatric ophthalmologists should actively look for intraocular vascular malformations as such findings can poorly affect a patient's vision.

Effect of Penetration Angle and Velocity During Intravitreal Injection on Pain.

Purpose: To evaluate the effect of velocity and angle of the intravitreal injection of anti-vascular endothelial growth factors on pain sensation.Methods: Patients were randomly assigned to one of four injection methods: straight and fast, straight and slow, tunneled and fast, and tunneled and slow. Later, they graded their pain sensation on a Visual Analog Scale (range 0-10).Results: The cohort included 180 patients. Mean pain score was 2.81 ± 2.34. There was no statistically significant difference in mean pain score among the four groups (p = .858); between the slow-injection (straight and tunneled) and fast-injection groups (p = .514); and between the straight-injection (fast and slow) and tunneled-injection groups (p = .992), nor other background variables.Conclusion: Velocity and angle of intravitreal injections are unrelated to the pain sensation. Therefore, the method may be left to the clinician's discretion. This implies that the sensation is mostly subjective.

A 12-month prospective study to evaluate the efficacy of using the treat-and-extend regimen with intravitreal aflibercept as a Second-Line Treatment for Diabetic Macular Oedema (the TADI Study).

PURPOSE: To evaluate the efficacy of intravitreal aflibercept as a second-line therapy in eyes with persistent diabetic macular oedema (DMO) despite receiving initial bevacizumab treatment. METHODS: A prospective multicentre study was conducted in nine academic clinics in Israel. Starting from the first follow-up visit, a treat-and-extend regimen was applied in which the treatment intervals were extended by 2 weeks based on macular thickness using SD-OCT. The primary outcome was central subfield thickness (CST) at week 52. RESULTS: Forty-four patients (n = 48 eyes) were recruited to the study, and 43 eyes completed 52 weeks of follow-up. Patients received a mean (±SD) of 7.9 ± 3.5 bevacizumab injections before enrolment. The mean (±SD) CST under aflibercept therapy decreased from 468 ± 131 µm at baseline to 303 ± 67 µm at 52 weeks (p = 0.002), and best corrected visual acuity improved from 64 ± 15 ETDRS letters at baseline to 75 ± 8 letters at week 52 (p = 0.001). Twenty (46%) eyes met the treat-and-extend criteria and received a mean (±SD) of 10.9 ± 2 aflibercept injections. CONCLUSIONS: Eyes with persistent DMO following initial bevacizumab therapy had a marked reduction in macular thickness and improved visual acuity following 1 year of treatment with intravitreal aflibercept. Less than half of the patients met eligibility criteria for extension of the treatment interval; for these patients, the treat-and-extend regimen resulted in a maximum treatment interval of 10 weeks during the first year.

Is Performing Femtosecond Laser-Assisted In Situ Keratomileusis on the Day of the Initial Consultation Visit Safe, Predictable and Efficacious?

OBJECTIVES: Our aim is to evaluate the safety, efficacy, predictability, and clinical outcome of femtosecond laser-assisted in situ keratomileusis (FS-LASIK) procedures performed on the day of the initial consultation relative to procedures performed at subsequent visits. METHODS: A retrospective cohort study design was used. The study group included patients with myopia of different severities who were treated with FS-LASIK in 2013 through 2014 in an optical outpatient clinic of a large private medical service. Inclusion criteria were at least 18 years of age, a stable refraction for 12 months, no history of autoimmune disease, ocular surgery, or eye disease, and complete medical records. Background, clinical, and outcome data were collected from the patient files. RESULTS: Femtosecond laser-assisted in situ keratomileusis was performed in 80 patients (160 eyes) at the first visit and 361 patients (719 eyes) at a subsequent visit. The mean±SD spherical equivalent (SE) refraction before surgery was -3.74±2.03 D in the first-visit group and -3.73±1.87 D in the subsequent-visit group (P=0.99). Efficacy index values were 0.97±0.15 in the first-visit group and 0.98±0.13 in the subsequent-visit group (P=0.92), and corresponding safety index values were 0.99±0.15 and 0.99±0.12 (P=0.81). The final SE measured -0.09±0.58 D in the first-visit group and -0.19±0.55 D in the subsequent-visit group (P=0.05). Types and rates of complications were similar in the two groups. CONCLUSIONS: There is no significant difference in the results of refractive surgery with FS-LASIK between procedures performed at the initial or subsequent visits. In both conditions, FS-LASIK surgery is associated with excellent safety, efficacy, and predictability profiles.

Effect of different lens status on intraocular pressure elevation in patients treated with anti-vascular endothelial growth factor injections.

AIM: To assess the effect of lens status on sustained intraocular pressure (IOP) elevation in patients treated intravitreally with anti-vascular endothelial growth factor (VEGF) agents. METHODS: Data were retrospectively collected for all patients treated with intravitreal injections of anti-VEGF medication at a tertiary medical center in July 2015. Findings were analyzed by lens status during 6 months' follow-up. The main outcome measure was a sustained increase in IOP (≥21 mm Hg or change of ≥6 mm Hg from baseline on ≥2 consecutive visits, or addition of a new IOP-lowering medication during follow-up). RESULTS: A total of 119 eyes of 100 patients met the study criteria: 40 phakic, 40 pseudophakic, and 39 pseudophakic after Nd:YAG capsulotomy. The rate of sustained IOP elevation was significantly higher in the post-capsulotomy group (23.1%) than in the phakic/pseudophakic groups (8.1%; P=0.032), with no statistically significant differences among the 3 groups in mean number of injections, either total (P=0.82) or by type of anti-VEGF mediation (bevacizumab: P=0.19; ranibizumab: P=0.13), or mean follow-up time (P=0.70). CONCLUSION: Nd:YAG capsulotomy appears to be a risk factor for sustained IOP elevation in patients receiving intravitreal anti-VEGF injections. This finding has important implications given the growing use of anti-VEGF treatment and the irreversible effects of elevated IOP.

Research productivity across different ophthalmic subspecialties in the United States.

BACKGROUND: The purpose of this study was to compare the h-index, and subsequently the research productivity, among different ophthalmic subspecialties in the United States. METHODS: A cohort of over 15,000 academic ophthalmologists residing in the United States (US) was identified out of the physician list of the American Academy of Ophthalmology. Of them, 1000 ophthalmologists with at least one publication were randomly retrieved, 100 in each of the following 10 subspecialties: cataract, cornea/external disease, glaucoma, medical retina, neuro-ophthalmology, pediatric ophthalmology, plastic/reconstructive ophthalmology, refractive surgery, retina/vitreous surgery and uveitis. Data collected included: number of published papers, h-index score, annual increase in h-index and the mean number of authors on each paper. RESULTS: The mean h-index amongst all subspecialties was 9.87 ± 13.90, and the mean average annual increase in h-index was 0.22 ± 0.21. The mean number of papers published was 37.20 ± 80.08 and the mean number of authors on each paper was 3.39 ± 0.84. Uveitis was the most prolific subspecialty in mean number of papers (74.78 ± 131.37), in mean h-index (16.69 ± 20.00) and in mean annual increase in h-index (0.35 ± 0.28). The least fertile subspecialty with regards to research was cataract with 11.06 ± 27.65 mean number of papers, a mean h-index of 3.89 ± 5.84, and a mean annual increase in h-index of 0.11 ± 0.11. CONCLUSIONS: This study describes the research productivity in each ophthalmic subspecialty in the US, thus providing information on the research performance of each field and on the expected academic accomplishments within it.

Diabetic macular edema treated with ranibizumab following bevacizumab failure in Israel (DERBI study).

PURPOSE:: To evaluate the outcome of second-line intravitreal ranibizumab treatment in eyes with diabetic macular edema having persistent edema following initial therapy with intravitreal bevacizumab. METHODS:: Diabetic macular edema treated with ranibizumab following bevacizumab failure in Israel was a retrospective, multi-center study. Consecutive eyes with persistent diabetic macular edema following at least three previous intravitreal bevacizumab injections prior to intravitreal ranibizumab, at least three-monthly intravitreal ranibizumab injections and at least 12 months of follow-up were included. Data collected included demographics, ocular findings, diabetes control, details of intravitreal bevacizumab and ranibizumab injections, and visual and anatomical measurements before and after intravitreal ranibizumab treatment. RESULTS:: In total, 202 eyes of 162 patients treated at 11 medical centers across Israel were included. Patients received a mean (±standard deviation) of 8.8 ± 4.9 intravitreal bevacizumab injections prior to the switch to intravitreal ranibizumab. A mean of 7.0 ± 2.7 intravitreal ranibizumab injections were given during the 12 months following the switch to intravitreal ranibizumab. The median central subfield retinal thickness (±interquartile range) by spectral-domain optical coherence tomography decreased from 436 ± 162 µm at baseline to 319 ± 113 µm at month 12 (p < 0.001). Median logMAR visual acuity (±interquartile range) improved from 0.40 ± 0.48 at baseline to 0.38 ± 0.40 at month 12 (p = 0.001). Linear regression suggested that higher number of intravitreal ranibizumab injections and higher pre-switch central subfield retinal thickness were associated with favorable visual outcome. Higher number of intravitreal bevacizumab injections and the presence of intraretinal fluid before the switch lessened the odds of favorable outcome. CONCLUSION:: Switching from bevacizumab to ranibizumab in persistent diabetic macular edema was associated with anatomical improvement in the majority of eyes and ⩾2 lines of vision improvement in 22% of eyes.

Effect of Subretinal Fluid Drainage Using Perfluorocarbon During Retinal Detachment Repair on Postoperative Metamorphopsia.

BACKGROUND AND OBJECTIVE: To determine whether subretinal fluid drainage (SRF) using perfluorocarbon (PFC) during rhegmatogenous retinal detachment (RRD) repair reduces postoperative metamorphopsia. PATIENTS AND METHODS: Consecutive patients after RRD were evaluated for best-corrected visual acuity (BCVA), funduscopy, and metamorphopsia using M-CHARTS. Fundus autofluorescence and optical coherence tomography were performed. Clinical and operative data were collected. RESULTS: The cohort included 30 patients, of whom 11 (36.7%) underwent intraoperative PFC injection. Rates of macula-off RRD were similar in the two groups (54.5% and 47.4%, P = .705). No association was found between PFC injection and metamorphopsia score. Preoperative macula-off RRD was associated with significantly higher vertical and horizontal metamorphopsia scores than preoperative macula-on. BCVA was significantly worse in the patients with metamorphopsia (logMAR 0.15 vs. logMAR 0.04; P = .042) CONCLUSION: Intraoperative SRF drainage with PFC appears to have no beneficial effect on postoperative metamorphopsia. Metamorphopsia is associated with macular status. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e263-e270.].

Correlation between Interleukin-6 and Thrombin-Antithrombin III Complex Levels in Retinal Diseases.

PURPOSE: This study aims to evaluate and correlate the levels of interleukin-6 (IL-6) and thrombin-antithrombin III complex (TAT) in the vitreous of patients with different vitreoretinal pathologies. METHODS: Vitreous samples were collected from 78 patients scheduled for pars plana vitrectomy at a tertiary medical center. Patients were divided by the underlying vitreoretinal pathophysiology, as follows: macular hole (MH)/epiretinal membrane (ERM) (n = 26); rhegmatogenous retinal detachment (RRD) (n = 32); and proliferative diabetic retinopathy (PDR) (n = 20). Levels of IL-6 and TAT were measured by enzyme-linked immunosorbent assay and compared among the groups. RESULTS: A significant difference was found in the vitreal IL-6 and TAT levels between the MH/ERM group and both the PDR and RRD groups (P < 0.001 for all). Diabetes was associated with higher IL-6 levels in the RRD group. Different relationships between the IL-6 and TAT levels were revealed in patients with different ocular pathologies. CONCLUSION: Our results imply that variations in vitreal TAT level may be attributable not only to an inflammatory reaction or blood-retinal barrier breakdown, but also to intraocular tissue-dependent regulation of thrombin.

Short-Term Vitreoretinal Tamponade with Heavy Liquid Following Surgery for Giant Retinal Tear.

PURPOSE: To study the efficacy and outcomes of short-term postoperative vitreoretinal tamponade with perfluorocarbon heavy liquid in patients with giant retinal tear. MATERIALS AND METHODS: The study group consisted of 13 consecutive patients (13 eyes) who presented with giant retinal tear at a tertiary medical center in 2011-2015 and were treated with vitrectomy followed by short-term tamponade with perfluorocarbon heavy liquid. A minimum of 3 months' follow-up was required for inclusion. The medical charts were retrospectively reviewed for patient demographics, procedural specifics, anatomical attachment rates, pre- and postoperative visual acuity, and postoperative complications. RESULTS: The duration of perfluorocarbon tamponade ranged from 6 to 13 days (mean ± SD 10 ± 2 days). Follow-up time ranged from 3 to 44 months (mean ± SD 11 ± 11 months). Retinal reattachment was achieved intraoperatively in all patients. Repeated detachment with proliferative vitreoretinopathy occurred in one patient (8%), who underwent repeated vitrectomies. At the last follow-up visit, the retina was attached in all patients. Best-corrected visual acuity improved postoperatively compared with preoperatively in all three patients with macula-off retinal detachment (100%) and was equal to or better than the initial best-corrected visual acuity in 6 (60%) of the 10 patients with macula-on retinal detachment. Complications included increased intraocular pressure, cataract, and cystoid macular edema. CONCLUSIONS: Perfluorocarbon heavy liquid is a safe and effective material for short-term vitreoretinal tamponade following vitrectomy for giant retinal tear.

Possible involvement of NETosis in inflammatory processes in the eye: Evidence from a small cohort of patients.

Purpose: To evaluate whether NETosis is involved in cytokine-induced ocular inflammation and to track neutrophil extracellular traps (NET) complexes in patients with proliferative diabetic retinopathy (PDR). Methods: For the animal model, the eyes of C57BL/6J mice were intravitreally injected with interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), or saline. Histology and immunofluorescence staining for CD11b, neutrophil elastase (NE), myeloperoxidase (MPO), citrullinated histone 3 (H3Cit), and net-like structure were performed. Vitreous samples were collected from patients with PDR; the PDR1 group had no need for repeated surgical intervention, and the PDR2 group had repeated vitreous bleeding or other complication and controls. Levels of MPO, H3Cit-MPO, and NE-MPO complex were measured with enzyme-linked immunosorbent assay (ELISA). Results: Massive influx of CD11+ inflammatory cells, involving the anterior and posterior chambers, was observed in the murine eyes 24 h after the IL-8 or TNF-α injections. Cells excreted to their surroundings an extracellular net-like structure positive for NE, MPO, and H3Cit. H3Cit staining was abolished with the DNase I treatment, indicating the presence of extracellular DNA in the net-like structures. The vitreous samples of the patients with PDR2 contained statistically significantly higher levels of MPO (173±230) compared to those of the patients with PDR1 (12.0±33.0, p<0.05) or the controls (0.00, p<0.01). The levels of H3Cit-MPO and NE-MPO complexes were also statistically significantly higher in the patients with PDR2 (776.0±1274, 573.0±911.0, respectively) compared to those in the patients with PDR1 (0, p<0.05) and the controls (0, p<0.05). Conclusions: This study showed the existence of NETosis in cytokine-induced ocular inflammation in a mouse model and human samples. Furthermore, the extent of NET complex formation was higher in a subset of patients who exhibited more complicated PDR.

The Effectiveness of Intravitreal Ranibizumab in Patients with Diabetic Macular Edema Who Have Failed to Respond to Intravitreal Bevacizumab.

PURPOSE: To investigate the response to intravitreal ranibizumab after failure of intravitreal bevacizumab in patients with diabetic macular edema (DME). METHODS: Demographics, visual acuity (VA), central macular thickness (CMT), and HbA1C were retrospectively collected from DME patients treated with second-line intravitreal ranibizumab at a tertiary hospital in 2012-2013 and followed for at least 3 months. RESULTS: Twenty-two patients (26 eyes) were included in the study, with a mean (±SD) age of 66 ± 8.1 years and followed for an average of 28.36 months. The mean number of intravitreal bevacizumab injections was 7.3 ± 2.8, and of intravitreal ranibizumab injections 5.11 ± 2.4. After 3 ranibizumab injections, 57% of eyes showed improvement in VA. The change in VA was statistically significant (p = 0.044) in those eyes where the pretreatment acuity for the second-line therapy was <20/40 (logMAR 0.3). CMT decreased from 435.95 ± 83.28 to 373.69 ± 44.39 µm (p = 0.01). The number of ranibizumab injections was significantly correlated with the change in CMT (p = 0.037). CONCLUSION: Intravitreal treatment with ranibizumab can be efficacious in eyes with DME that have failed to respond to bevacizumab.

Bevacizumab clearance through the iridocorneal angle following intravitreal injection in a rat model.

Antivascular endothelial growth factor (Anti-VEGF) agents have been widely used for a variety of ocular disorders. The etiology of sustained ocular hypertension following intravitreal administration of anti-VEGF agents is yet to be unraveled. Our study investigates and characterizes the presence of intravitreally injected bevacizumab in the aqueous outflow channels of a rat model. Choroidal neovascularization (CNV) was induced by diode laser photocoagulation to the right eye of twelve Brown Norway rats. Bevacizumab (25 mg/ml) was injected intravitreally after 3 days. Immediately after bevacizumab injection, and 3, 6, 24 and 48 h later, animals were euthanized for immunofluorescence staining. Donkey anti-human IgG labeled with Alexa Fluor(®) 488 was used for bevacizumab immunoreactivity detection. Anti-CD31 antibody was used as a marker for Schlemm's canal endothelial cells. Untreated eyes were used as negative controls. The intensity of the immunostaining was analyzed qualitatively. Bevacizumab immunoreactivity was found in the aqueous outflow channels including the trabecular meshwork and Schlemm's canal immediately after injection, and declined incrementally within the following hours. Forty-eight hours after the injection, no bevacizumab staining was detected in the aqueous outflow channel structures. Our manuscript demonstrates the presence of bevacizumab in the trabecular meshwork and Schlemm's canal structures after intravitreal injection in a CNV induced rat model. Bevacizumab molecules passed through the aqueous outflow channels within 48 h after intravitreal bevacizumab injection.