Refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomized clinical trial.

IMPORTANCE: Children born prematurely who develop retinopathy of prematurity (ROP) often develop myopia, and those who require laser treatment may develop very high myopia, which has considerable clinical consequences. OBJECTIVE: To report refractive outcomes in preterm infants who developed ROP in zone I or zone II posterior as stage 3+ ROP or aggressive posterior ROP (APROP). DESIGN, SETTING, AND PARTICIPANTS: All infants received intravitreal bevacizumab or laser therapy in a prospective, stratified, randomized, controlled, masked, multicenter clinical trial, Bevacizumab Eliminates the Angiogenic Threat for ROP (BEAT-ROP). Children who received intravitreal bevacizumab or laser in the BEAT-ROP clinical trial, with treatment randomized by infant, underwent cycloplegic retinoscopic refraction at a mean age of 2½ years. Fifteen centers with both pediatric and vitreoretinal ophthalmologists participating in level 3 neonatal intensive care units in academic centers with institutional review board approval were included in the trial. Of the originally enrolled 150 infants (300 eyes) in the BEAT-ROP clinical trial, 13 infants (26 eyes) died (6 received intravitreal bevacizumab; 7 received laser) and 19 eyes had intraocular surgery (6 infants bilaterally). Thus, 45 eyes (19 infants bilaterally) were excluded, leaving 131 infants (255 eyes, including 21 eyes that received a successful second treatment for recurrence). INTERVENTIONS: Follow-up of the BEAT-ROP cohort. MAIN OUTCOMES AND MEASURES: Spherical equivalent refractive outcomes and their distribution by ROP zone and treatment. RESULTS: Refractions were available for 109 of 131 eligible infants (83.2%) and 211 of 255 eyes (82.7%). Mean (SD) spherical equivalent refractions were as follows: zone I, -1.51 (3.42) diopters (D) in 52 eyes that received intravitreal bevacizumab and -8.44 (7.57) D in 35 eyes that received laser treatment (P < .001); and zone II posterior, -0.58 (2.53) D in 58 eyes that received intravitreal bevacizumab and -5.83 (5.87) D in 66 eyes that received laser treatment (P < .001). Very high myopia (≥-8.00 D) occurred in zone I in 2 of 52 (3.8%) eyes that received intravitreal bevacizumab and in 18 of 35 (51.4%) eyes that received laser treatment (P < .001). Very high myopia occurred in zone II posterior in 1 of 58 (1.7%) eyes that received intravitreal bevacizumab and in 24 of 66 (36.4%) eyes that received laser treatment (P < .001). CONCLUSIONS AND RELEVANCE: More very high myopia was found in eyes that received laser treatment than in eyes that received intravitreal bevacizumab. This difference is possibly related to anterior segment development that is present with intravitreal bevacizumab but minimal or absent following laser treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00622726.

Influence of subretinal fluid in advanced stage retinopathy of prematurity on proangiogenic response and cell proliferation.

PURPOSE: The clinical phenotype of advanced stage retinopathy of prematurity (ROP, stages 4 and 5) cannot be replicated in an animal model. To dissect the molecular events that can lead up to advanced ROP, we examined subretinal fluid (SRF) and surgically dissected retrolental membranes from patients with advanced ROP to evaluate its influences on cell proliferation, angiogenic properties, and macrophage polarity. METHODS: We compared our findings to SRF collected from patients with uncomplicated rhegmatogenous retinal detachment (RD) without proliferative vitreoretinopathy and surgically dissected epiretinal membrane from eyes with macular pucker. All subretinal fluid samples were equalized for protein. The angiogenic potential of SRF from ROP eyes was measured using a combination of capillary cord formation in a fibrin clot assay, and its proliferative effect was tested with a DNA synthesis of human retinal microvascular endothelial cells. Findings were compared with SRF collected from participants with uncomplicated rhegmatogenous RD without proliferative vitreoretinopathy. The ability of SRF to induce nitric oxide production was measured in vitro using murine J774A.1 macrophages. Cytokine profiles of SRF from ROP and RD eyes were measured using a multienzyme-linked immunosorbent assay (ELISA). Fluorescent immunohistochemistry of retrolental membranes from ROP was performed to detect the presence of leukocytes and the composition of tissue macrophages using markers for M1 and M2 differentiation. RESULTS: The cytokine composition in SRF revealed that in ROP, not only were several proangiogenic factors were preferentially elevated but also the profile of proinflammatory factors was also increased compared to the RD eyes. SRF from ROP eyes supported cell proliferation and endothelial cord formation while SRF from RD eyes had inhibitory effects. SRF from eyes with ROP but not RD robustly induced nitric oxide production in macrophages. Furthermore, fluorescent immunostaining revealed a preponderance of M1 over M2 macrophages in retrolental fibrous membranes from ROP eyes. The cytokine profile and biologic properties of SRF in ROP promote a proangiogenic environment, which supports the maintenance and proliferation of fibrous membranes associated with advanced stages of ROP. In contrast, SRF from RD eyes exhibits a suppressive environment for endothelial cell proliferation and angiogenesis. CONCLUSIONS: Our investigation demonstrates that the microenvironment in advanced ROP eyes is proangiogenic and proinflammatory. These findings suggest that management of advanced ROP should not be limited to the surgical removal of the fibrovascular membranes and antiangiogenic therapy but also directed to anti-inflammatory therapy and to promote M2 activation over M1 activity.

Immunohistochemical study of chronic nongranulomatous anterior uveitis in juvenile idiopathic arthritis.

PURPOSE: To provide a detailed immunohistochemical analysis of juvenile idiopathic arthritis (JIA)-associated anterior uveitis. DESIGN: Interventional case report. PARTICIPANT: One patient. INTERVENTION: A 12-year-old patient had recurrent pauciarticular JIA and smoldering anterior uveitis in the right eye. Despite treatment with local and systemic corticosteroids and an anti-tumor necrosis factor agent, the right eye became hypotonous and painful and eventually was enucleated. The clinical history and histopathologic and immunohistochemical analyses of the enucleated globe were reviewed. MAIN OUTCOME MEASURES: Histopathologic and immunohistochemical features of JIA-associated anterior uveitis. RESULTS: The iris and ciliary body showed nongranulomatous chronic inflammation predominantly made up of plasma cells, Russell bodies, and plasmacytoid lymphocytes. The ciliary processes and pars plana ciliaris showed focal aggregates of CD20-positive cells with several CD3- and CD8-positive cells and occasional CD4- and CD68-positive cells. Pancytokeratin stain showed ciliary epithelial proliferation admixed with lymphocytes. The iris revealed kappa-positive cells within the stroma and lambda-positive cells on the surface. The iris infiltrate primarily was made up of immunoglobulin (Ig) G-positive cells with occasional IgA- and IgM-positive cells. The anterior chamber exudate was mainly positive for IgG and IgA. CONCLUSIONS: The immunohistochemical findings suggest that JIA-associated nongranulomatous iridocyclitis is a primarily B-cell-infiltrative process.

Intravitreal bevacizumab (Avastin) for post laser anterior segment ischemia in aggressive posterior retinopathy of prematurity.

Aggressive posterior retinopathy of prematurity (formerly known as fulminate/type II/rush disease) occurs in zone 1 or posterior zone 2. Treatment involves extensive near confluent laser ablation of a large area of avascular retina. Anterior segment ischemia is a rare complication that can occur due to injury to the long posterior ciliary arteries in the horizontal meridians during aggressive posterior laser treatment. The outcome of this rare complication is very poor. This case describes a favorable outcome of intravitreal injection of bevacizumab (Avastin) in a case of anterior segment ischemia.

Vitreoretinal complications of retinoblastoma treatment.

PURPOSE: To describe complications of the retina and vitreous occurring in children undergoing treatment for retinoblastoma and their clinical management. METHODS: Retrospective analysis of Ret-Cam images of 206 patients with retinoblastoma treated at one center between 1996 and 2003. Images were studied for vitreoretinal features other than tumor persistence or recurrence. Specifically, complications such as vitreous, retinal, or choroidal hemorrhage, retinal detachment, retinal fold, vascular obstruction, and preretinal or subretinal proliferation were sought. RESULTS: Vitreoretinal complications of retinoblastoma therapy were identified in 14 patients (6.8%) All had heritable bilateral retinoblastoma. Group 5 Reese-Ellsworth disease was present in 50% (n = 7). All patients had systemic chemotherapy, 50% had external beam radiotherapy, and 64% had more than one local treatment method. Of the 14 patients with a complication, 4 eyes were enucleated for massive recurrence of tumor, 5 eyes were observed, and 5 eyes were treated successfully with vitreoretinal surgery for tractional or rhegmatogenous retinal detachment. CONCLUSION: Vitreoretinal complications occurred in 6.8% of patients undergoing therapy for retinoblastoma. These included retinal tears, rhegmatogenous and tractional retinal detachment, subretinal fibrosis, vitreous traction bands, preretinal fibrosis, and pseudo-vitreous seeding. They were more often seen when systemic chemotherapy was combined with external beam radiation, cryotherapy, and local chemotherapy.

Evaluation of open globe injuries of children in the last 12 years.

PURPOSE: To determine whether advances in vitreoretinal surgical techniques developed over the last decade have translated into improved anatomic and visual outcomes. METHODS: Retrospective review of children under the age of 18 who were treated for open globe injuries at a children's hospital between January 1990 and December 2002. RESULTS: The authors identified 59 open globe injuries seen at a single center in the past 12 years. Thirty eyes (51%) required secondary surgery after primary closure. Twelve patients underwent pars plana vitrectomy (PPV), and all presented with an initial visual acuity of count fingers or worse. Seven (58%) had an improvement in vision to 20/200 or better, and 6 (50%) of these patients achieved a visual acuity of 20/50 or better. CONCLUSION: Improvements in outcome compared to previous studies may signify refinement in technique and an increased utility of PPV over the last 10 years.

Intravenous foscarnet in the management of acyclovir-resistant herpes simplex virus type 2 in acute retinal necrosis in children.

BACKGROUND: Diagnosis and management of Acute Retinal Necrosis (ARN) in children that does not respond to systemic acyclovir treatment can be challenging. We report two cases of ARN secondary to herpes simplex virus (HSV) type 2 that was resistant to acyclovir but was treated successfully with intravenous foscarnet. CASE REPORT: Two children diagnosed with ARN failed to show clinical response to systemic acyclovir treatment. Both cases had histories of previous HSV infections and vitreous taps positive for HSV-2. Both were converted to systemic foscarnet treatment with successful control of the retinitis and satisfactory visual outcomes. CONCLUSIONS: Systemic foscarnet can be effective in the management of pediatric acute retinal necrosis caused by HSV-2 when there is an atypical response to conventional acyclovir treatment.

Subfoveal nodule in Coats' disease.

An atypical presentation of Coats' disease is reported with a prominent subfoveal nodule with peripheral retinal exudates. A 6-year old boy presented with 6/120 vision in the left eye associated with an elevated 1 mm subfoveal, circular lesion with peripheral exudates. The fluorescein angiogram showed peripheral retinal telangiectasias with leakage consistent with Coats' disease. The prominent subfoveal nodule is an uncommon initial presentation of Coats' disease and physicians should be aware of this atypical finding.

Focal inner retinal hemorrhages in patients with drusen: an early sign of occult choroidal neovascularization and chorioretinal anastomosis.

PURPOSE: To present evidence that superficial retinal hemorrhage in the macula of patients with age-related macular degeneration (ARMD) may be an early sign of occult chorioretinal anastomosis (OCRA) and type 1 occult choroidal neovascularization (OCNV). METHODS: Retrospective follow-up study of 16 patients presenting with a small focal area of superficial retinal hemorrhages and drusen in the juxtafoveolar area in 24 eyes. RESULTS: OCRA and OCNV occurred in an older subset of patients with ARMD (mean age, 75 years). Of 22 eyes with the early stages of chorioretinal anastomosis (CRA), 18 had evidence of a piggyback neovascular complex, with the smaller subsensory retinal type 2 complex lying anterior to the larger subretinal pigment epithelial type 1 complex. At initial presentation, three patients had OCRA and OCNV bilaterally, and three patients had large disciform cicatricial lesions with overt CRA in the fellow eye. Nine patients had one or more laser photocoagulation treatments for early stages of CRA. Only one patient maintained visual acuity of better than 20/200 for >1 year. At the last follow-up, 24 of 26 eyes with CRA had visual acuity of 20/200 or less. CONCLUSION: Superficial retinal hemorrhage in the paracentral area of patients with drusen is the earliest sign of OCRA and OCNV. Fluorescein angiography and indocyanine green angiography are important in detecting the dual nature of the subretinal neovascular network. Photocoagulation and photodynamic treatment is usually unsuccessful in preserving central vision.

Macular features of pediatric surgical vitreoretinal diseases.

We discuss herein several pediatric vitreoretinal diseases that have characteristic macular features. Although some of these changes are subtle, they offer important diagnostic and prognostic information. Most of these conditions require close follow-up and timely surgical intervention. Several important surgical considerations are mentioned.