Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema.

BACKGROUND: In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear. METHODS: At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed. RESULTS: A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group. CONCLUSIONS: In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).

Proliferative vitreoretinopathy may be a risk factor in combined macular hole retinal detachment cases.

OBJECTIVE: To review the incidence and closure rate of full-thickness macular holes (MH) in cases associated with concomitant rhegmatogenous retinal detachment (RRD). METHODS: A retrospective consecutive case series was performed from patients undergoing surgical repair of RRD and simultaneous closure of MH. The presence of proliferative vitreoretinopathy (PVR), rates of hole closure and reattachment, and visual acuity outcomes were evaluated. RESULTS: There were a total of 607 RRDs during the study period. The incidence of concomitant MH in RRD cases was 2.3% (14 of 607), and the overall incidence of PVR was 15.8% (96 of 607). All eyes with a MH had a primary break that was distinct from the MH. Five patients did not meet the inclusion criteria for review of the postoperative outcomes. In the remaining 9 patients, the retinal reattachment rate was 100%, and MH closure was achieved in 8 of 9 (89%) eyes after a single surgery. At the time of primary repair, PVR was present in 6 of these 9 cases (66.7%). There was a significant association between the presence of PVR and a concomitant MH (P = 0.0027). The mean preoperative visual acuity was 2.59 ± 0.649 logarithm of the minimum angle of resolution units and significantly improved to 1.23 ± 1.01 logarithm of the minimum angle of resolution units (P = 0.00124). Overall, 88.8% of patients showed an improvement in visual acuity at the final postoperative visit, and a visual acuity of 20/125 or better was achieved in 66.7% of cases. CONCLUSION: Macular holes combined with a RRD are infrequent, and good anatomical results can be achieved after a simultaneous repair. Also, PVR may be more frequently encountered in this particular subset of RRDs.

Small-Gauge Pars Plana Vitrectomy for Visually Significant Vitreous Floaters.

Purpose: This article evaluates our experience at a retina-only private practice with small-gauge pars plana vitrectomy (PPV) for visually significant vitreous floaters. We review the surgical outcomes, complication rates, and percentage of second-eye surgery for the same indication. Methods: A retrospective, interventional case series was conducted of consecutive patients undergoing PPV for significant vitreous floaters from September 2014 to December 2018 at a high-volume vitreoretinal surgery practice. Preoperative visual acuity (VA), complication rates, and visual outcome following surgery were evaluated. Results: A total of 104 eyes in 81 patients underwent PPV for visually significant floaters; 35 (43.2%) patients had PPV in both eyes. Mean preoperative VA was 0.16 ± 0.17 logMAR (∼20/29 Snellen equivalent) and improved to 0.12 ± 0.15 logMAR (∼20/26 Snellen; Wilcoxon test, P = .008) at the last follow-up after PPV. All patients had improvement in VA at the final postoperative visit, with a VA of 20/40 or better achieved in 93.3% of cases. The complication rate of vitreous hemorrhage postoperatively was 0.96%. There were no cases of postoperative retinal tears, breaks, or endophthalmitis. Conclusions: Small-gauge PPV in the carefully selected patient is an effective and safe procedure to eliminate symptoms. VA following PPV for vitreous floaters significantly improved. Nearly half of the patients studied (43.2%) underwent PPV in the other eye.

The Scope Of Three-Dimensional Digital Visualization Systems In Vitreoretinal Surgery.

INTRODUCTION: Significant advances in three-dimensional (3D) imaging technology have allowed for the incorporation of 3D digital displays into medical and surgical devices. Despite initial adoption of the NGENUITY® 3D Visualization System in vitreoretinal surgery, there are limited publications regarding its use. The generally accepted main benefits include improved ergonomics, enhanced surgical team communication and education, reduced retinal phototoxicity, increased depth of field, and display image manipulation. Despite these potential benefits, many retina specialists have questioned its universal applicability to a wide variety of vitreoretinal surgeries. OBJECTIVE: To report on the variety of indications and surgical efficacy of the NGENUITY® 3D Visualization System in vitreoretinal surgery via a review of surgical experience at two vitreoretinal practices in both the academic and community settings. METHODS: A retrospective review was conducted of consecutive surgical cases performed on the NGENUITY® 3D Visualization System at Massachusetts Eye and Ear Infirmary and Florida Retina Institute from June 1st, 2017 to November 1st, 2018. Age, presenting diagnosis, surgical procedure, and intraoperative details were recorded. RESULTS: 272 vitreoretinal surgeries on the Alcon NGENUITY® 3D Visualization System were identified between June 1st, 2017 and November 1st, 2018 at the participating institutions. A detailed breakdown of the indications for surgery and related procedures is reported. During all 272 cases on the 3D digital system, there were no complications attributed to the visualization system. CONCLUSION: This series illustrates the diversity of vitreoretinal surgeries that can be performed on this system without compromising surgical viewing or increasing surgical complications. The Alcon NGENUITY® 3D Visualization System possesses favorable ergonomics, illumination levels, depth of field, display filters, and trainee experience.

Intravitreal steroids for macular edema: the past, the present, and the future.

Macular edema, a condition usually associated with an underlying disease process, is a common cause of severe visual loss. There have been a variety of approaches to the treatment of macular edema; within the past few years, however, intravitreal corticosteroid treatments have emerged as an increasingly used treatment option for patients with macular edema. Intravitreal delivery allows the steroid to bypass the blood-retinal barrier, leading to a more concentrated dose of steroid for a prolonged period of time. Corticosteroids have likely been successful in the treatment of various forms of macular edema, due to their known anti-angiogenic, anti-edematous, anti-inflammatory, anti-apoptotic, and anti-proliferative effects. Intravitreal triamcinolone acetonide has been repeatedly successful in reducing macular edema and improving visual acuity, although the duration of action is typically short-term. Due to the recurrent and chronic nature of macular edema, biodegradable implants may be the future of intravitreal steroids. Intravitreal corticosteroids are not without risks. Steroid-related side effects include cataract formation and elevated intraocular pressure. Injection-related side effects include retinal detachment, vitreous hemorrhage, bacterial endophthalmitis, and sterile endophthalmitis. This article reviews the evolving role of intravitreal corticosteroids in the treatment of macular edema secondary to uveitis, diabetes, and retinal vascular disorders.

ACANTHAMOEBA ENDOPHTHALMITIS AFTER RECURRENT KERATITIS AND NODULAR SCLERITIS.

PURPOSE: To describe the clinical course of a patient with Acanthamoeba keratitis, who despite prompt treatment progressed to histopathology-confirmed Acanthamoeba retinitis and endophthalmitis. METHODS: Case report. RESULTS: A healthy 30-year-old male wearing soft contact lens was diagnosed with Acanthamoeba keratitis and treated medically and surgically over the course of 1 year with presumed resolution of the infection. Yet, his infection recurred with documented spread to sclerokeratitis, and overwhelming endophthalmitis. Concerns about extra-ocular spread prompted a therapeutic enucleation with histopathologic evidence of Acanthamoeba organisms throughout the globe. CONCLUSION: This is a case of a severe recurrent Acanthamoeba infection presenting initially as keratitis, followed by sclerokeratitis and histolopathology-confirmed endophthalmitis. This case demonstrates that despite persistent medical and surgical intervention, eradication of organisms may not be possible.

Bilateral Retinal Detachments After Intravitreal Injection of Adipose-Derived 'Stem Cells' in a Patient With Exudative Macular Degeneration.

A 77-year-old woman with exudative macular degeneration underwent bilateral intravitreal injections of "stem cells" at a clinic in Georgia. One month and 3 months after injection, she developed retinal detachments in the left and right eyes, respectively. Increased awareness within the medical community of such poor outcomes is critical so that clinics offering untested practices that have been shown to be potentially harmful to patients can be identified and brought under U.S. Food and Drug Administration oversight. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:772-775.].

Retinal detachment in a patient with leber congenital amaurosis.

PURPOSE: To report the unique presentation of a patient with Leber congenital amaurosis who developed a tractional retinal detachment involving the macula and underwent successful pars plana vitrectomy surgery. METHODS: Retrospective interventional case report. Chart review. RESULTS: A 54-year-old white woman, with molecularly confirmed CEP290-associated Leber congenital amaurosis, who initially presented with Snellen visual acuity of 20/200 in the right eye and 20/125 in the left eye and constricted visual fields. The maculae were flat, the vessels were attenuated, and the periphery was flat with diffuse atrophic changes and bone spicule-like pigmentation in both eyes. Follow-up examination, 3 years later, demonstrated a temporal tractional retinal detachment in the left eye, which involved the macula; however, the vision was stable. She presented 4 months later, and her vision declined to light perception in the left eye and the traction retinal detachment now involved the entire macula. A pars plana vitrectomy was performed, and 8 months later, the visual acuity improved to 20/300 in the left eye and the periphery was attached 360° with extensive bone spicule-like pigmentation and laser scars. CONCLUSION: Leber congenital amaurosis is a rare inherited retinal disease that can be complicated by tractional retinal detachment. Vitrectomy surgery can be used successfully to repair retinal detachments in this patient population. The patient had subsequent improvement in visual acuity and anatomical reattachment.

OX40 ligand expression abrogates the immunosuppressive function of retinal pigment epithelium.

BACKGROUND: This study aims to investigate the role of OX40 ligand (OX40L) in ocular inflammation via abrogation of retinal pigment epithelium (RPE)-mediated immunosuppression using an in vitro expression approach. OX40L cDNA was polymerase chain reaction-amplified and cloned into an eYFP fusion vector. Cultured retinal pigment epithelial cells (ARPE-19) were transfected with the vector. Total RNA from unstimulated or inflammatory cytokine-stimulated ARPE cells were isolated and analyzed for OX40L expression by reverse transcription-polymerase chain reaction. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy human donors. Human ARPE cells (±OX40L ± GITR ligand (GITRL) expression) and PBMCs were co-cultured for in vitro proliferation studies. RESULTS: Polymerase chain reaction confirmed the insertion of the OX40L gene into the fusion vector. Flow cytometry and fluorescence microscopy further confirmed surface expression of OX40L on ARPE cells after transfection. OX40L expression was induced in the RPE cells stimulated with pro-inflammatory cytokines. In the co-culture studies, there was a significant reversal (20% to 30%) of the RPE-induced suppression of activated PBMCs when the ARPE cells were transfected with OX40L. When both OX40L and GITRL were concomitantly transfected into ARPE cells, there was an additive reversal of RPE-mediated T cell suppression, when compared to the reversal caused by RPE cells expressing either OX40L alone or GITRL alone. CONCLUSIONS: Using an in vitro approach, we found that OX40L causes an abrogation of the RPE-mediated immunosuppression. OX40L appears to be regulated in the ARPE-19 cell line and may play an important role in the pathogenesis of various ocular inflammatory conditions.

Sequential, acute noninfectious uveitis associated with separate intravitreal injections of bevacizumab and ranibizumab.

PURPOSE: To report the unique response of a patient with exudative age-related macular degeneration who developed sequential episodes of acute noninfectious uveitis following separate intravitreal injections of bevacizumab and ranibizumab. METHODS: Retrospective interventional case report. Chart review. RESULTS: A 73-year-old white woman, who received monthly intravitreal bevacizumab injections for exudative age-related macular degeneration in the right eye, developed decreased vision 4 days after her last injection. She had trace anterior chamber cells and 1+ vitritis, consistent with a bevacizumab-associated uveitis. The patient improved on topical steroids and cycloplegics. Subsequently, her exudative age-related macular degeneration was treated with monthly ranibizumab injections. Optical coherence tomography demonstrated persistent subretinal fluid despite treatment. Seven days after her 11th ranibizumab injection, she developed sudden decreased vision, 2+ anterior chamber cell, and 4+ vitritis. Presumptive treatment for an exogenous bacterial endophthalmitis was given after a vitreous biopsy was performed, which demonstrated severe sterile infiltrates that were culture negative. All injections were stopped. Three months later, the subretinal fluid had disappeared, the vitritis has nearly resolved, but some intraretinal fluid persisted. CONCLUSION: Acute noninfectious uveitis, a known risk following injection with either bevacizumab or ranibizumab, may develop sequentially in the same patient, suggesting the possibility of cross-sensitivity. Additionally, spontaneous anatomical improvement after uveitis from antibody-based vascular endothelial growth factor inhibition implies a suppressive immunomodulatory effect on vascular permeability or choroidal neovascularization. The availability of agents with alternative molecular structures, such as aflibercept, may permit additional insights into the complex relationship between choroidal neovascularization, vitritis, and innate and other immunologic processes.

Management and outcome of microbial anterior scleritis.

PURPOSE: To evaluate the prevalence, predisposing factors, and outcomes of bacterial and fungal scleritis. METHODS: We reviewed the clinical findings, therapeutic interventions, and visual outcomes of patients with suppurative scleral inflammation without preceding microbial keratitis who had microorganisms isolated from scleral scrapings. DESIGN: Retrospective interventional case series. RESULTS: Of 349 patients with scleritis diagnosed from 1999 to 2009, 6 adults (1.7%) presented with suppurative inflammation of the anterior sclera due to Pseudomonas aeruginosa (2), Streptococcus pneumoniae (2), Staphylococcus aureus (1), and Scedosporium apiospermum/Pseudallescheria boydii (1). Each had ocular surgery of the affected eye before presentation. Intraocular extension occurred in 2 eyes. After local and systemic antimicrobial therapy, all improved without evisceration or enucleation, and 4 attained vision of 20/60 or better. CONCLUSIONS: Bacterial or fungal scleritis is an uncommon ocular infection that can belatedly follow anterior segment procedures. Antimicrobial therapy and surgical intervention can successfully control progressive suppuration and reduce vision-limiting complications.

TSLP and downstream molecules in experimental mouse allergic conjunctivitis.

PURPOSE: To explore the potential role of thymic stromal lymphopoietin (TSLP) and its downstream molecules in the development of ocular allergic inflammation using a short ragweed (SRW)-induced mouse model of allergic conjunctivitis (AC). METHODS: BALB/c mice were topically challenged with SRW pollen after they were sensitized with SRW in the footpad. After the last SRW challenge, the corneal epithelium, conjunctiva, and cervical lymph nodes were harvested for total RNA extraction and gene expression by RT and real-time PCR, and whole eye globes were collected to make cryosections for immunohistochemical staining. RESULTS: Repeated topical challenges with SRW allergen generated typical signs of AC in mice. Compared with the untreated controls, TSLP mRNA expression and immunoreactivity were significantly increased in the corneal and conjunctival epithelia of SRW-induced AC mice. CD11c(+) and OX40L(+) immunoreactive cells largely infiltrated the conjunctiva with increased mRNA levels of CD11c, TSLPR, and OX40L detected in the corneal epithelium, conjunctiva, and cervical lymph nodes. CD4(+) Th2 cell infiltration was evidenced by increased levels of mRNA and immunoreactivity of CD4, IL-4, IL-5, and IL-13 in the ocular surface, mainly in the conjunctiva, accompanied by increased expression of OX40, STAT6, and GATA3, in AC mice. The maturation of immature DCs was observed with the use of TSLP containing conditioned media from corneal epithelial cultures exposed to polyI:C, which stimulates TSLP production. CONCLUSIONS: This study provides new findings regarding the role of local mucosal epithelial cells in the initiation of ocular allergic inflammation by producing a novel proallergic cytokine, TSLP, which activates dendritic cells to prime Th2 differentiation and allergic inflammation through the TSLP-TSLPR and OX40L-OX40 signaling pathway.

LX211 (voclosporin) suppresses experimental uveitis and inhibits human T cells.

PURPOSE: To test the therapeutic effectiveness of voclosporin against experimental autoimmune uveoretinitis (EAU) in rats and to evaluate its effect on human T cells. METHODS: EAU was induced by immunization with a uveitogenic protein. Voclosporin administration, by subcutaneous injection, began on day (d) 0 or d7 after immunization. Treatment effectiveness was evaluated in vivo using clinical EAU scoring (d7-d13) and histopathologic evaluation of enucleated eyes after experimental termination. Rodent lymphocytes were harvested from lymph nodes on d14 for antigen-specific proliferation assays. The effect of voclosporin on human T-cell proliferation and cytokine secretion was examined in vitro. RESULTS: Voclosporin prevented EAU development in rats receiving medium and high preventive doses, whereas high-dose voclosporin administration effectively treated EAU. Lymphocytes from animals treated with voclosporin had decreased antigen-specific proliferation in vitro compared with lymphocytes from untreated animals. No evidence of abnormal ocular histopathology was found in the eyes from animals that received high doses of therapeutic voclosporin. Using human T cells, voclosporin inhibited human T-cell proliferation up to 100-fold. Furthermore, voclosporin treatment of human T cells significantly reduced pan T-cell effector responses. CONCLUSIONS: Voclosporin effectively suppressed uveoretinitis in an animal model that imitates the human inflammatory ocular disease by inhibiting lymphocyte proliferation. In addition, voclosporin effectively inhibited human T-cell proliferation and function in vitro. The authors report the first evidence supporting the application of voclosporin to treat intraocular inflammation.

CD4+Foxp3+ T-regulatory cells in noninfectious uveitis.

OBJECTIVE: To evaluate CD4(+)Foxp3(+) (forkhead box P3) T-regulatory cell populations in patients with uveitis and to determine if T-regulatory cell populations are associated with disease features. METHODS: Patients with uveitis were evaluated for CD4(+)Foxp3(+) T-regulatory cells by flow cytometry. Systemic and ocular diagnoses, disease activity, and the presence of cystoid macular edema were reviewed. Percentages of CD4(+)Foxp3(+) lymphocytes were compared for patients with inactive vs active disease, systemic vs ocular diagnoses, and the presence or absence of cystoid macular edema. Real-time polymerase chain reaction testing was performed on 2 patients with extremely low CD4(+)Foxp3(+) cell populations to assess Foxp3 mRNA. RESULTS: A total of 20 patients with intermediate uveitis, posterior uveitis, and panuveitis were evaluated. The mean age was 40.6 years and the mean visual acuity was 20/57. Percentages of CD4(+)Foxp3(+) cells were lower in patients with active compared with inactive uveitis (P< .05). No differences in T-regulatory cells were observed between the other subgroups. Two patients with recalcitrant uveitis who demonstrated less than 1% CD4(+)Foxp3(+) lymphocytes showed extremely low or absent Foxp3 mRNA. CONCLUSION: T-regulatory cells are reduced in patients with active compared with inactive disease. Severe depletion of CD4(+)Foxp3(+) T cells and Foxp3 mRNA in 2 patients with severe uveitis suggests that loss of the T-regulatory cells of uveitis may be a salient feature in certain patients.