BACKGROUND: To evaluate changes in image sharpness across ultrawide field (UWF) images and the effect of phase-plate adjustment on image contrast and extent of visible retinal area (VRA). METHODS: This was a single site evaluation of 200° UWF images acquired with phase-plate adjustment (California, Optos, plc) and without (200TX, Optos, plc). Images were acquired using standardized protocol. VRA was manually outlined on each image and quantified using customized software. Mean image sharpness was evaluated using an automated method within the full VRA of each image and within the peripheral region of the VRA. The VRA and image sharpness were evaluated and compared between the two devices. RESULTS: Twenty eyes of 10 healthy volunteers were evaluated. Devices with and without phase-plate adjustment produced a similar extent of VRA. Eye steering increased VRA in devices with and without phase-plate adjustment by 39.3% and 34.3%, respectively. Regardless of gaze direction, mean sharpness of the full VRA was reduced in peripheral area with or without phase-plate adjustment. Compared to images without phase-plate adjustment, use of phase-plate adjustment reduced the loss of peripheral image sharpness in all fields (-4.2 to -26.0%; p < 0.001 all fields). The sharpness of the peripheral area for on-axis images was 61.5% higher with phase-plate adjustment. CONCLUSIONS: The use of phase-plate adjustment does not alter the extent of VRA. However, for on-axis images the loss of sharpness in the periphery is 4.5-fold less with phase-plate adjustment, potentially reducing the need to steer images and improving lesion detection in these areas.

PURPOSE: To assess the effect of intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents on immediate and long-term intraocular pressure (IOP) elevation and glaucoma. METHODS: Literature searches of the PubMed and Cochrane databases, last conducted in April 2018, yielded 253 unique citations. Of these, 41 met the inclusion criteria and were rated according to the strength of evidence. Two articles were rated level I, 17 were rated level II, and 15 were rated level III; an additional 7 were excluded because of poor study design and lack of relevance to the topic under evaluation. RESULTS: The studies that reported on short-term IOP elevation (i.e., between 0 and 60 minutes) showed that an immediate increase in IOP is seen in all patients when measured between 0 and 30 minutes of intravitreal injection and that the IOP elevation decreases over time. The data on long-term IOP elevation were mixed; 7 studies reported that between 4% and 15% of patients developed sustained elevation of IOP at 9 to 24 months after injection, whereas 6 studies found no long-term change in IOP from 1 to 36 months after injection. Pretreatment with glaucoma medications, anterior chamber tap, vitreous reflux, longer intervals between injections, and longer axial lengths were associated with lower IOP elevations after injection. Data were mixed on the relationship between IOP increase and the type of intravitreal injection, number of intravitreal injections, preexisting glaucoma, and globe decompression before injection. There were no data on the onset or progression of glaucoma in the studies reviewed in this assessment. CONCLUSIONS: Intravitreal injection of anti-VEGF agents results in an immediate and transient increase in IOP. A long-term increase in IOP also may be seen, and further studies are needed to determine at-risk populations. Although there is some suggestion in the literature, there is currently insufficient data to determine the impact of intravitreal anti-VEGF injections on glaucoma progression. Although pretreatment with glaucoma medications, performing anterior chamber paracentesis, or increasing the interval between injections may reduce the impact of transient IOP elevation, the clinical significance and associated risks of these interventions are unknown.

OBJECTIVE: To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. STUDY DESIGN: This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 23 weeks to 27 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 29 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 40 weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. RESULTS: Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. CONCLUSIONS: rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01096784.

Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is the most bothersome symptom accompanying an attack. Using subjective psychophysical assessments, we showed that migraine patients are more sensitive to all colors of light during ictal than during interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in both phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual-evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b wave, which was consistently larger (by 14%-19% in the light-adapted and 18%-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a wave or the visual-evoked potentials that differs most strikingly between the 2 groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that nonmigraineurs feel as if they are in a cave.

PURPOSE: To ascertain the incidence of unexpected management changes at the postoperative week 1 visit in asymptomatic patients who have had an uncomplicated cataract surgery and a routine postoperative day 1 examination. DESIGN: Retrospective observational study. METHODS: A retrospective chart review was conducted of all cases of cataract extraction by phacoemulsification with intraocular lens insertion performed by the Comprehensive Ophthalmology Service at Massachusetts Eye and Ear between January 1, 2014 and December 31, 2014. The preoperative consultation, operative report, and postoperative day 1 and week 1 (postoperative days 5-14) visits were reviewed. Cases with intraoperative complications, as well as clinical findings at postoperative day 1 requiring close follow-up, were excluded. The main outcome measure was incidence of unexpected management changes at the postoperative week 1 visit after cataract surgery, defined as an unanticipated change in postoperative drops, additional procedures, or urgent referral to a specialty service. RESULTS: Overall, 1938 surgical cases of 1471 patients were reviewed, and 1510 cases (77.9%) underwent uncomplicated phacoemulsification with intraocular lens implantation with a routine postoperative day 1 examination. Of these 1510 cases, 238 (15.8%) reported symptoms at the postoperative week 1 visit, including flashes, floaters, redness, pain, or decreased vision, which warranted an examination. In total, 1272 cases were asymptomatic, and only 11 of these cases (0.9%) had an unexpected management change at postoperative week 1. Eight of 11 patients were asymptomatic steroid responders requiring alteration of their postoperative drops. Two of these patients had an intraocular pressure >30 mm Hg. CONCLUSIONS: Unexpected management changes at the postoperative week 1 timepoint after cataract surgery are rare in asymptomatic patients who have had uncomplicated cataract surgery and a routine postoperative day 1 examination. Limited data are available to outline an optimal postoperative regimen after cataract surgery. The results of this study suggest that postoperative week 1 examinations could potentially be performed on an as-needed basis in the appropriate subgroup of patients after cataract surgery.

PURPOSE: To test the effects of an encapsulated cell-based delivery of a neuroprotective agent, ciliary neurotrophic factor (CNTF), on progression of macular telangiectasia type 2, a neurodegenerative disease with no proven effective therapy. DESIGN: Randomized sham-controlled clinical trial. PARTICIPANTS: Ninety-nine study eyes of 67 eligible participants were enrolled. METHODS: Single-masked randomized clinical trial of 24 months' duration conducted from May 2014 through April 2017 in 11 clinical centers of retinal specialists in the United States and Australia. Participants were randomized 1:1 to surgical implantation of intravitreal sustained delivery of human CNTF versus a sham procedure. MAIN OUTCOME MEASURES: The primary outcome was the difference in the area of neurodegeneration as measured in the area of the ellipsoid zone disruption (or photoreceptor loss) measured on spectral-domain (SD) OCT images at 24 months from baseline between the treated and untreated groups. Secondary outcomes included comparison of visual function changes between treatment groups. RESULTS: Among the 67 participants who were randomized (mean age, 62±8.9 years; 41 women [61%]; 58 white persons [86%]), 65 (97%) completed the study. Two participants (3 study eyes) died and 3 participants (4 eyes) were found ineligible. The eyes receiving sham treatment had 31% greater progression of neurodegeneration than the CNTF-treated eyes. The difference in mean area of photoreceptor loss was 0.05±0.03 mm (P = 0.04) at 24 months. Retinal sensitivity changes, measured using microperimetry, were correlated highly with the changes in the area of photoreceptor loss (r = 0.86; P < 0.0001). The mean retinal sensitivity loss of the sham group was 45% greater than that of the treated group (decrease, 15.81±8.93 dB; P = 0.07). Reading speed deteriorated in the sham group (-13.9 words per minute) with no loss in the treated group (P = 0.02). Serious adverse ocular effects were found in 2 of 51 persons (4%) in the sham group and 2 of 48 persons (4%) in the treated group. CONCLUSIONS: In participants with macular telangiectasia type 2, a surgical implant that released CNTF into the vitreous cavity, compared with a sham procedure, slowed the progression of retinal degeneration. Further research is needed to assess longer-term clinical outcomes and safety.

Neutrophil-mediated inflammation plays a critical role in corneal damage following injury or infection. Previous studies demonstrated that membrane-bound FasL (mFasL) induces neutrophil chemokine production. However, the extracellular domain of mFasL is normally cleaved by matrix metalloproteinases to release a soluble form of FasL (sFasL) and sFasL antagonizes mFasL-mediated chemokine production. Therefore, we hypothesized that sFasL could be used to prevent neutrophil-mediated corneal inflammation associated with injury and bacterial keratitis. To test this hypothesis, GFP-only, sFasL-GFP, or mFasL-GFP were expressed in the corneal stroma of C57BL/6 mice, using intra-stromal injections of plasmid DNA or adenoviral vectors (AV) and the role of mFasL and sFasL in corneal inflammation was examined in models of corneal injury and LPS-induced keratitis. Our work addresses an important area of disagreement in the field of FasL, with regard to the mechanism by which sFasL regulates ocular inflammation. Herein, we demonstrate that an intrastromal injection of GFP-only, sFasL-GFP, or mFasL-GFP plasmid DNA resulted in GFP expression throughout the corneal stroma for up to two weeks with little to no evidence of inflammation in the GFP-only and sFasL-GFP groups and mild corneal inflammation in the mFasL-GFP group. Similarly, following epithelial debridement, corneas expressing GFP-only or sFasL-GFP showed no significant signs of corneal inflammation, with clear corneas at 15 days post debridement. By contrast, epithelial debridement of corneas expressing mFasL-GFP triggered persistent corneal inflammation and the development of central corneal opacities that was blocked by sFasL. Similar to the mFasL-GFP plasmid DNA, intrastromal injection of mFasL-GFP AV triggered mild corneal inflammation, but it was transient and resolved by day 10 with corneas remaining clear out to 30 days post injection. Nevertheless, intrastromal expression of mFasL-GFP AV exacerbated LPS-induced keratitis, corneal opacity, and neovascularization, while sFasL-GFP AV expression prevented LPS-induced keratitis, resulting in a clear cornea. Histological analysis of corneas with LPS-induced keratitis revealed a robust infiltration of macrophages and neutrophils and sFasL expression specifically blocked the neutrophil influx. Overall, our data demonstrate that stromal expression of mFasL is inflammatory, while sFasL is non-inflammatory, and opposes the effects of mFasL in mouse models of epithelial debridement and LPS-induced keratitis. These data demonstrate that a delicate balance between sFasL and mFasL regulates ocular inflammation. This study further identifies sFasL as a potent inhibitor of neutrophil-mediated corneal damage, and supports the potential use of sFasL in the treatment of neutrophil-mediated keratitis. These results strongly support the hypothesis that, in the immune privileged environment of the eye, the isoform of FasL regulates immune privilege and determines the extent of inflammation: mFasL promotes inflammation and sFasL blocks inflammation.

PURPOSE: To compare visual acuity (VA) improvement in children aged 7 to 12 years with amblyopia treated with a binocular iPad game plus continued spectacle correction vs. continued spectacle correction alone. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: One hundred thirty-eight participants aged 7 to 12 years with amblyopia (33-72 letters, i.e., approximately 20/200 to 20/40) resulting from strabismus, anisometropia, or both. Participants were required to have at least 16 weeks of optical treatment in spectacles if needed or demonstrate no improvement in amblyopic-eye visual acuity (VA) for at least 8 weeks prior to enrollment. METHODS: Eligible participants (mean age 9.6 years, mean baseline VA of 59.6 letters, history of prior amblyopia treatment other than spectacles in 96%) were randomly assigned to treatment for 8 weeks with the dichoptic binocular Dig Rush iPad game (prescribed for 1 hour per day 5 days per week) plus spectacle wear if needed (n = 69) or continued spectacle correction alone if needed (n = 69). MAIN OUTCOME MEASURES: Change in amblyopic-eye VA from baseline to 4 weeks, assessed by a masked examiner. RESULTS: At 4 weeks, mean amblyopic-eye VA letter score improved from baseline by 1.3 (2-sided 95% confidence interval [CI]: 0.1-2.6; 0.026 logMAR) with binocular treatment and by 1.7 (2-sided 95% CI: 0.4-3.0; 0.034 logMAR) with continued spectacle correction alone. After adjusment for baseline VA, the letter score difference between groups (binocular minus control) was -0.3 (95% CI: -2.2 to 1.5, P = 0.71, difference of -0.006 logMAR). No difference in letter scores was observed between groups when the analysis was repeated after 8 weeks of treatment (adjusted mean: -0.1, 98.3% CI: -2.4 to 2.1). For the binocular group, adherence data from the iPad indicated that slightly more than half of the participants (58% and 56%) completed >75% of prescribed treatment by the 4- and 8-week visits, respectively. CONCLUSIONS: In children aged 7 to 12 years who have received previous treatment for amblyopia other than spectacles, there was no benefit to VA or stereoacuity from 4 or 8 weeks of treatment with the dichoptic binocular Dig Rush iPad game.