Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of Single-Dose Tafenoquine in Healthy Volunteers.

INTRODUCTION: Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria. OBJECTIVE: This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina. METHODS: This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers. Adult healthy volunteers were randomized (2:1) to receive either a single 300-mg oral dose of tafenoquine or matched placebo on day 1. Ophthalmic assessments, including spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF), were conducted at baseline and day 90 and evaluated for pre-determined endpoints by an independent, masked reading center. RESULTS: One subject in each group met the composite primary endpoint for retinal changes identified with SD-OCT or FAF, i.e., one out of 306 (0.3%) with tafenoquine, one out of 161 (0.6%) with placebo. Both cases had unilateral focal ellipsoid zone disruption at day 90 with no effect on best-corrected visual acuity. The tafenoquine-treated subject had this abnormality at baseline, and was enrolled in error. There was no difference in ophthalmic safety between tafenoquine and placebo. CONCLUSION: There was no evidence of any pharmacodynamic effect of 300-mg single-dose tafenoquine on the retina or any short-term clinically relevant effects on ophthalmic safety. This clinical trial is registered with ClinicalTrials.gov (identifier: NCT02658435).

Long-term outcomes in ranibizumab-treated patients with retinal vein occlusion; the role of progression of retinal nonperfusion.

PURPOSE: To determine the percentage of ranibizumab-treated patients with retinal vein occlusion (RVO) who had resolution of edema for at least 6 months after the last injection, along with factors and outcomes that correlate with resolution. DESIGN: Post hoc analysis of open-label clinical trial. METHODS: Twenty patients with branch RVO (BRVO) and 20 with central RVO (CRVO) received ranibizumab monthly for 3 months and as needed for recurrent/persistent macular edema, no more frequently than every 2 months. Patients still requiring injections after month 40 received scatter and grid laser photocoagulation to try to reduce the need for injections. Main outcome measures included the percentage of patients who had resolution of edema, change in best-corrected visual acuity (BCVA) from baseline, and change in area of retinal nonperfusion in central subfields. RESULTS: Nine patients with BRVO (45%) had edema resolution from injections alone after a mean of 20.2 months, 4 resolved after addition of laser, 4 were unresolved through 72 months, and 3 exited prior to resolution. Five patients with CRVO (25%) resolved from injections alone after a mean of 14.0 months, 8 remained unresolved through 72 months despite addition of laser, and 7 exited prior to resolution. For BRVO or CRVO, there was a negative correlation between posterior retinal nonperfusion area and BCVA at months 18, 24, and 36 (P < .05). CONCLUSIONS: In patients with RVO, infrequent ranibizumab injections to control edema may not be sufficient to prevent progression of retinal nonperfusion, which may contribute to loss of visual gains.

VEGF secreted by hypoxic Müller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy.

In proliferative diabetic retinopathy (PDR), retinal ischemia promotes neovascularization (NV), which can lead to profound vision loss in diabetic patients. Treatment for PDR, panretinal photocoagulation, is inherently destructive and has significant visual consequences. Therapies targeting vascular endothelial growth factor (VEGF) have transformed the treatment of diabetic eye disease but have proven inadequate for treating NV, prompting exploration for additional therapeutic options for PDR patients. In this regard, extracellular proteolysis is an early and sustained activity strictly required for NV. Extracellular proteolysis in NV is facilitated by the dysregulated activity of matrix metalloproteinases (MMPs). Here, we set out to better understand the regulation of MMPs by ischemia in PDR. We demonstrate that accumulation of hypoxia-inducible factor-1α in Müller cells induces the expression of VEGF, which, in turn, promotes increased MMP-2 expression and activity in neighboring endothelial cells (ECs). MMP-2 expression was detected in ECs in retinal NV tissue from PDR patients, whereas MMP-2 protein levels were elevated in the aqueous of PDR patients compared with controls. Our findings demonstrate a complex interplay among hypoxic Müller cells, secreted angiogenic factors, and neighboring ECs in the regulation of MMP-2 in retinal NV and identify MMP-2 as a target for the treatment of PDR.

Choroidal neovascularization in Bardet-Biedl syndrome.

PURPOSE: To describe a case of choroidal neovascularization in a young patient with genetically-proven Bardet-Biedl syndrome. METHODS: Case description with fundus and anatomical photography and optical coherence tomography. PATIENTS: Single patient case description. RESULTS: Fundus photography and optical coherence tomography reveal the presence of previously-active choroidal neovascularization. Anatomical, historical, and genetic evidence confirm Bardet-Biedl syndrome in this individual. DISCUSSION: Choroidal neovascularization accompanying this syndrome has not been reported. Herein we describe the first published description of choroidal neovascularization in an individual with genetically-proven Bardet-Biedl syndrome.

Treatment of Coats' disease with intravitreal bevacizumab.

OBJECTIVE: To compare the efficacy of intravitreal bevacizumab plus ablative therapy with ablative therapy alone for Coats' disease. METHODS: A retrospective review of all paediatric patients who received treatment for Coats' disease from a single surgeon (GBH) from 1 January 2001 to 31 March 2010 was performed. Ten consecutive patients who received intravitreal bevacizumab as part of their treatment were matched to 10 patients treated with ablative therapy alone by macular appearance, quadrants of subretinal fluid, and quadrants of telangiectasias. Outcomes evaluated were number of treatment sessions, time to full treatment, and resolution of disease. RESULTS: There was no statistical difference between baseline characteristics when comparing the bevacizumab and control groups. Eyes treated with bevacizumab required more treatments over a longer time period compared to the control group. All patients in the bevacizumab group were successfully treated while two of the patients in the control group failed ablative techniques. CONCLUSIONS: Intravitreal bevacizumab may play a role as adjuvant therapy in select cases of Coats' disease, but its use does not reduce the time to full treatment. Resolution of disease was seen in the most severe cases treated with bevacizumab plus thermal ablation whereas their matched controls failed therapy with laser and cryotherapy alone.

Evaluation and management of pediatric rhegmatogenous retinal detachment.

Pediatric rhegmatogenous retinal detachments are rare, accounting for less than ten percent of all rhegmatogenous retinal detachments. While most retinal detachments in the adult population are related to posterior vitreous detachment, pediatric retinal detachment are often related to trauma or an underlying congenital abnormalities or genetic syndrome. The anatomy of pediatric eyes, the often late presentation of the disease, and the high incidence of bilateral pathology in children all pose significant challenges in the management of these patients. We discuss the epidemiology of pediatric rhegmatogenous retinal detachment, review the genetic syndromes associated with a high incidence of retinal detachment, and examine other common causes of retinal detachment in this age group. We then outline an approach to evaluation and management and describe the expected outcomes of repair of retinal detachment in the pediatric population.

Intraoperative microscope-mounted spectral domain optical coherence tomography for evaluation of retinal anatomy during macular surgery.

OBJECTIVE: To evaluate the use of microscope mounted spectral domain optical coherence tomography (SD-OCT) to detect changes in retinal anatomy during macular surgery. DESIGN: Retrospective, observational case series. PARTICIPANTS: We included 25 eyes of 24 consecutive patients who underwent SD-OCT during macular surgery. METHODS: A retrospective review of operative techniques, outcomes, and imaging for all patients who underwent intraoperative microscope mounted SD-OCT during surgery for macular hole or epiretinal membrane (ERM) from April 2009 to April 2010 was performed. Qualitative and quantitative characteristics of intraoperative and postoperative changes in retinal anatomy were studied. MAIN OUTCOME MEASURES: Intraoperative change in macular hole dimensions and retinal thickness in patients with ERM owing to surgical manipulation measured using SD-OCT. RESULTS: Intraoperative SD-OCT from 13 eyes of 13 patients undergoing surgery for macular hole was reviewed. Two cases had images of suboptimal quality and were excluded. The remaining 11 eyes were subjected to quantitative analysis, which revealed stability of macular hole height and central hole diameter after internal limiting membrane (ILM) peeling, but an increase in the diameter of subretinal fluid under the macula in ten of 11 eyes (average 87% wider). Intraoperative imaging from 12 eyes of 11 patients undergoing surgery for ERM was analyzed. Quantitative analysis revealed an average increase of retinal thickness after ILM peel of <2%. Ten of 12 eyes developed a new subretinal hyporeflectance, which likely represents shallow detachment of the macula, after uncomplicated membrane peel. CONCLUSIONS: Use of intraoperative SD-OCT has provided new insight into the changes to retinal anatomy during macular surgery and may prove to be a useful tool for vitreoretinal surgery. Further study is warranted to determine whether intraoperative changes such as the creation of shallow retinal detachments during uncomplicated macular surgery affects visual recovery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Epstein-barr infection of the retina: case report and review of the literature.

PURPOSE: The purpose of this study is to describe a presumed case of Epstein-Barr virus (EBV) infection of the retina in a 65-year-old female with sudden bilateral vision loss. METHODS: Diagnostic vitreous biopsy of the left eye was performed to test for EBV and other known infectious causes of retinitis and evaluate vitreous cells. RESULTS: Serologic EBV testing was positive. Vitreous polymerase chain reaction viral DNA testing was positive for EBV, but negative for herpes-simplex virus, varicella-zoster virus, cytomegalovirus, and toxoplasma gondii. Histopathologic analysis of vitreous cells revealed atypical lymphocytes. CONCLUSIONS: Epstein-Barr virus may be a cause of retinal disease. Awareness of this severe ocular complication may enable prompt diagnosis and treatment of future cases, and promote greater investigation into its disease prevalence.

Biliverdin reductase: a major physiologic cytoprotectant.

Bilirubin, an abundant pigment that causes jaundice, has long lacked any clear physiologic role. It arises from enzymatic reduction by biliverdin reductase of biliverdin, a product of heme oxygenase activity. Bilirubin is a potent antioxidant that we show can protect cells from a 10,000-fold excess of H2O2. We report that bilirubin is a major physiologic antioxidant cytoprotectant. Thus, cellular depletion of bilirubin by RNA interference markedly augments tissue levels of reactive oxygen species and causes apoptotic cell death. Depletion of glutathione, generally regarded as a physiologic antioxidant cytoprotectant, elicits lesser increases in reactive oxygen species and cell death. The potent physiologic antioxidant actions of bilirubin reflect an amplification cycle whereby bilirubin, acting as an antioxidant, is itself oxidized to biliverdin and then recycled by biliverdin reductase back to bilirubin. This redox cycle may constitute the principal physiologic function of bilirubin.