Judy E. Kim

Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema

OBJECTIVE To report 3-year outcomes of patients who participated in a randomized trial evaluating 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone compared with focal/grid photocoagulation for treatment of diabetic macular edema. METHODS Eyes with diabetic macular edema and visual acuities of 20/40 to 20/320 were randomly assigned to focal/grid photocoagulation or 1 mg or 4 mg of triamcinolone. At the conclusion of the trial, 3-year follow-up data were available in 306 eyes. RESULTS Between 2 years (time of the primary outcome) and 3 years, more eyes improved than worsened in all 3 treatment groups. Change in visual acuity letter score from baseline to 3 years was +5 in the laser group and 0 in each triamcinolone group. The cumulative probability of cataract surgery by 3 years was 31%, 46%, and 83% in the laser and 1-mg and 4-mg triamcinolone groups, respectively. Intraocular pressure increased by more than 10 mm Hg at any visit in 4%, 18%, and 33% of eyes, respectively. CONCLUSIONS Results in a subset of randomized subjects who completed the 3-year follow-up are consistent with previously published 2-year results and do not indicate a long-term benefit of intravitreal triamcinolone relative to focal/grid photocoagulation in patients with diabetic macular edema similar to those studied in this clinical trial. Most eyes receiving 4 mg of triamcinolone as given in this study are likely to require cataract surgery. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00367133.

Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents.

PURPOSE To assess short-term trends and the need to monitor intraocular pressure (IOP) changes immediately after intravitreal injections of ranibizumab, bevacizumab, pegaptanib, and triamcinolone acetonide. DESIGN Retrospective, interventional case series. METHODS Charts of 213 consecutive injections to 120 eyes of 112 patients were reviewed. Pressures were measured before injection, immediately after injection (T0), and at five-minute intervals until IOP was less than 30 mm Hg. Optic nerve perfusion was assessed by testing for hand movement vision and by indirect ophthalmoscopic examination. Kaplan-Meier and Chi-square analyses of IOP after injections and correlation of IOP spikes to drug, needle bore size, injection volume, and history of glaucoma were performed. RESULTS Mean preinjection IOP was 14 mm Hg (range, 7 to 22 mm Hg). Mean IOP at T0 was 44 mm Hg (range, 4 to 87 mm Hg). All but one eye had at least hand movement vision and a perfused optic nerve at T0. IOP was reduced to less than 30 mm Hg in 96% of injections by 15 minutes and in 100% by 30 minutes. Eyes with a history of glaucoma took longer to normalize the IOP (P = .002). Statistically significant IOP spikes were observed with a smaller needle bore size (P < .0001) and in eyes with a history of glaucoma (P = .001). CONCLUSIONS Elevations in IOP immediately after intravitreal injections are common, but are transient. Prolonged monitoring of IOP may not be necessary on the day of injection in most cases if hand movement vision, optic nerve perfusion, and lack of intraocular complications have been verified. However, cautious monitoring should be considered in select cases.

Retained Lens Fragments after Phacoemulsification

PURPOSE The authors present the clinical features of patients with retained lens fragments after phacoemulsification and their outcome after pars plana vitrectomy. METHODS The authors performed a retrospective chart review of 62 patients who had surgical management of posteriorly dislocated lens fragments after phacoemulsification during the 3-year period from January 1990 to December 1992. RESULTS Eight of the 62 patients underwent vitrectomy on the same day as the cataract surgery. Of the remaining 54 patients examined in the outpatient clinic, initial clinical features included marked intraocular inflammation (87%), elevated intraocular pressure of 30 mmHg or higher (46%), and corneal edema (46%). Retinal detachment was present before vitrectomy in one patient and occurred after vitrectomy in two others. Initial visual acuity was 20/200 or worse in 68% of patients. After vitrectomy, final visual acuity was 20/40 or better in 68% of patients. Using the percentage of patients with 20/40 or better final visual acuity, there was no statistically significant difference in surgery performed within 7 days (70%), between 1 and 4 weeks (60%), and after 4 weeks (70%). Twenty (80%) of 25 patients with initial posterior chamber intraocular lenses (PC IOLs) and 16 (62%) of 26 patients with initial anterior chamber IOLs (AC IOLs) achieved 20/40 or better visual acuity. A visual acuity outcome of 20/200 or worse occurred in all three patients with retinal detachment. Six of the eight patients who underwent vitrectomy on the same day as the cataract surgery achieved 20/30 or better visual acuity. CONCLUSIONS The timing of vitrectomy did not influence visual acuity outcomes. Intraocular lenses inserted at the primary operation did not adversely affect the visual outcome. However, vitrectomy on the same day as cataract surgery generally yielded favorable visual acuity outcomes and eliminated the need for a second operation at a later date. In most patients with retained lens fragments, management with vitrectomy allowed good visual acuity outcomes.

Randomized Trial of a Home Monitoring System for Early Detection of Choroidal Neovascularization Home Monitoring of the Eye (HOME) Study

OBJECTIVE To determine whether home monitoring with the ForeseeHome device (Notal Vision Ltd, Tel Aviv, Israel), using macular visual field testing with hyperacuity techniques and telemonitoring, results in earlier detection of age-related macular degeneration-associated choroidal neovascularization (CNV), reflected in better visual acuity, when compared with standard care. The main predictor of treatment outcome from anti-vascular endothelial growth factor (VEGF) agents is the visual acuity at the time of CNV treatment. DESIGN Unmasked, controlled, randomized clinical trial. PARTICIPANTS One thousand nine hundred and seventy participants 53 to 90 years of age at high risk of CNV developing were screened. Of these, 1520 participants with a mean age of 72.5 years were enrolled in the Home Monitoring of the Eye study at 44 Age-Related Eye Disease Study 2 clinical centers. INTERVENTIONS In the standard care and device arms arm, investigator-specific instructions were provided for self-monitoring vision at home followed by report of new symptoms to the clinic. In the device arm, the device was provided with recommendations for daily testing. The device monitoring center received test results and reported changes to the clinical centers, which contacted participants for examination. MAIN OUTCOME MEASURES The main outcome measure was the difference in best-corrected visual acuity scores between baseline and detection of CNV. The event was determined by investigators based on clinical examination, color fundus photography, fluorescein angiography, and optical coherence tomography findings. Masked graders at a central reading center evaluated the images using standardized protocols. RESULTS Seven hundred sixty-three participants were randomized to device monitoring and 757 participants were randomized to standard care and were followed up for a mean of 1.4 years between July 2010 and April 2013. At the prespecified interim analysis, 82 participants progressed to CNV, 51 in the device arm and 31 in the standard care arm. The primary analysis achieved statistical significance, with the participants in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection (median, -4 letters; interquartile range [IQR], -11.0 to -1.0 letters) compared with standard care (median, -9 letters; IQR, -14.0 to -4.0 letters; P = 0.021), resulting in better visual acuity at CNV detection in the device arm. The Data and Safety Monitoring Committee recommended early study termination for efficacy. CONCLUSIONS Persons at high risk for CNV developing benefit from the home monitoring strategy for earlier detection of CNV development, which increases the likelihood of better visual acuity results after intravitreal anti-VEGF therapy.

Differentiating Macular Holes from Macular Pseudoholes

Surgical treatments of macular holes have become increasingly effective in inducing resolution of the cuff of surrounding subretinal fluid, resulting in increased vision in many patients. However, for many conditions that mimic a macular hole, either surgery is not indicated or different surgical manipulations are necessary. Differentiating macular holes from some forms of macular pseudoholes can be difficult or impossible based solely on clinical examination. Adjunctive tests that may enhance the accuracy of diagnosis are either not feasible or not available to most clinical practices. We evaluated three clinic-based tests for their value in allowing the differentiation between macular holes and macular pseudoholes: Amsler grid testing, Watzke-Allen sign, and laser aiming beam test. These tests were evaluated in three groups of clinically defined patients: those with full-thickness macular holes, those with macular pseudoholes, and those who had previously undergone successful macular hole treatment. Although the Amsler grid testing was sensitive in correlating with clinically defined macular holes, it was not specific. The Watzke-Allen sign and, to a greater extent, the laser aiming beam test were extremely sensitive and specific in correlating clinically defined full-thickness macular holes and pseudoholes. These tests improve the accuracy of diagnosis of full-thickness macular holes.

ISIS-DME: a prospective, randomized, dose-escalation intravitreal steroid injection study for refractory diabetic macular edema.

Purpose: To determine safety and efficacy of intravitreal triamcinolone acetonide (IVTA) for refractory clinically significant diabetic macular edema (DME). Design: Prospective, randomized, dose-escalation pilot study comparing single injection of 2 mg versus 4 mg doses of IVTA. Methods: Inclusion criteria included clinically significant DME persisting ≥3 months after maximal laser treatment and visual acuity ≤20/40. Best-corrected ETDRS vision, intraocular pressure, presence of DME, and fluorescein angiography (FA) were evaluated at 3 months and 6 months after injection. Results: Mean change in visual acuity at 3 months compared to baseline was 7.1 letters (P = 0.01) in the 2 mg group and 12.5 letters in the 4 mg group (P < 0.0001). However, there was not a significant difference in visual improvement between the 2 mg and 4 mg dose groups (P = 0.11). Vision improved >15 letters at 3 months in 23% (3/13) of 2 mg group and in 33% (5/15) of 4 mg group (P = 0.69), and 0% (0/11) and 21% (3/14) at 6 months, respectively (P = 0.23). Visual improvement was more likely in cystoid-type DME than diffuse DME. Intraocular pressure rise of ≥10 mmHg occurred in 19% (3/16) of 2 mg group and 41% (7/17) of 4 mg group. Conclusions: Both doses of IVTA were well tolerated and had significant positive effects on refractory DME for short term. There were consistent trends throughout the study that suggest that a 4 mg IVTA may be more effective than a 2 mg dose. The benefit of IVTA was greater for cystoid-type DME.

Safety profile of ocriplasmin for symptomatic vitreomacular adhesion: A comprehensive analysis of premarketing and postmarketing experiences

Purpose: After the recent approval of ocriplasmin by the Food and Drug Administration, postmarketing safety concerns have been raised by the vitreoretinal community. The American Society of Retina Specialists Therapeutic Surveillance Committee was commissioned to monitor postmarketing drug-related and device-related adverse events. The purpose of this report is to analyze the postmarketing safety experience in the context of available premarketing safety data. Methods: Periodic aggregate safety reports consisting of premarketing, or clinical trial, data (n = 999 injections) and postmarketing reports through July 16, 2013 (n = 4,387 injections), were retrospectively analyzed by the TSC. The aggregate data were analyzed to classify adverse events, and the postmarketing safety data for each event type were compared with the premarketing data. Results: Eight categories of adverse events were identified. Acute reduction in visual acuity attributable to either worsening of macular pathology or development of subretinal fluid, electroretinogram changes, dyschromatopsia, retinal tears and detachments, lens subluxation or phacodonesis, impaired pupillary reflex, and retinal vessel findings were reported in both the premarketing and postmarketing experiences. Ellipsoid zone (inner segment/outer segment) findings were only reported in the postmarketing experience. Rates of postmarketing reports were lower than in the premarketing data. Adverse events were generally transient, and characteristics of these adverse events were generally similar between the premarketing and postmarketing experience. Conclusion: Postmarket analyses are limited by significant underreporting, and in the case of ocriplasmin as a first in-class drug, they may not have captured safety events that have only more recently been identified. Nonetheless, postmarket analyses can identify the scope of potential safety events based on real-world experiences. Ocriplasmin administration should be guided by an appropriate and informed risk-benefit discussion with the patient. Ongoing active postmarket surveillance by all practitioners will continue to be critical to better understand this safety profile.

Endophthalmitis in Patients with Retained Lens Fragments after Phacoemulsification

PURPOSE To review the treatment and outcomes of patients presenting with concurrent endophthalmitis and retained lens fragments after phacoemulsification. METHODS A retrospective chart review was conducted on patients presenting with culture-proven endophthalmitis and retained lens fragments after phacoemulsification between 1990 and 1994. RESULTS Five patients were identified with culture-proven endophthalmitis and retained lens fragments after phacoemulsification. In all patients, coagulase-negative staphylococci were cultured from the vitreous fluid. One patient also had positive cultures for Proteus mirabilis and Escherichia coli. The interval between cataract surgery and treatment ranged from 5 days to 6 months. Echography was beneficial in showing retained lens fragments in five of five patients when media opacities obscured the view of the fundus. Four patients had vitrectomy and removal of retained lens fragments during their initial treatment. The fifth patient was treated with intravitreal antibiotics alone and continued to have marked inflammation, eventually requiring vitrectomy for removal of the retained lens fragments. A final visual acuity of 20/400 or better was achieved in four of the five patients. CONCLUSIONS Patients may present with endophthalmitis in the setting of retained lens fragments after phacoemulsification. In such cases, the preferred initial management may be pars plana vitrectomy, removal of retained lens fragments, and injection of intraocular antibiotics. In eyes with endophthalmitis and opaque media, echography is a useful screening modality.

Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study System for Evaluation of Stereoscopic Color Fundus Photographs and Fluorescein Angiograms: SCORE Study Report 9

OBJECTIVE To describe the procedures and reproducibility for grading stereoscopic color fundus photographs and fluorescein angiograms of participants in the SCORE Study. METHODS Standardized stereoscopic fundus photographs and fluorescein angiograms taken at 84 clinical centers were evaluated by graders at a central reading center. Type of retinal vein occlusion (RVO), area of retinal thickening, and area of retinal hemorrhage are evaluated from fundus photographs; area of fluorescein leakage and area of capillary nonperfusion are measured on fluorescein angiography. Temporal reproducibility consisted of annual regrading of a randomly selected dedicated subset of fundus photographs (60 subjects) and fluorescein angiograms (40 subjects) for 3 successive years. Contemporaneous reproducibility involved monthly regrading of a 5% random selection of recently evaluated fundus photographs (n = 73). RESULTS The intergrader agreement for RVO type and presence of retinal thickening was greater than 90% in the 3 annual regrades. The intraclass correlation (ICC) for area of retinal thickening in the 3 years ranged from 0.39 to 0.64 and for area of retinal hemorrhage, 0.87 to 0.96. The ICC for area of fluorescein leakage ranged from 0.66 to 0.75 and for capillary nonperfusion, 0.94 to 0.97. The contemporaneous reproducibility results were similar to those of temporal reproducibility for all variables except area of retinal thickening (ICC, 0.84). CONCLUSIONS The fundus photography and fluorescein angiography grading procedures for the SCORE Study are reproducible and can be used for multicenter longitudinal studies of RVO. A systematic temporal drift occurred in evaluating area of retinal thickening.

Repeated Intravitreous Ranibizumab Injections for Diabetic Macular Edema and the Risk of Sustained Elevation of Intraocular Pressure or the Need for Ocular Hypotensive Treatment

IMPORTANCE For the management of retinal disease, the use of intravitreous injections of anti-vascular endothelial growth factor has increased. Recent reports have suggested that this therapy may cause sustained elevation of intraocular pressure (IOP) and may potentially increase the risk of glaucoma for patients with retinal disease. OBJECTIVE To assess the risk of sustained IOP elevation or the need for IOP-lowering treatments for eyes with diabetic macular edema following repeated intravitreous injections of ranibizumab. DESIGN, SETTING, AND PARTICIPANTS An exploratory analysis was conducted within a Diabetic Retinopathy Clinical Research Network randomized clinical trial. Study enrollment dates were from March 20, 2007, to December 17, 2008. Of 582 eyes (of 486 participants) with center-involved diabetic macular edema and no preexisting open-angle glaucoma, 260 were randomly assigned to receive a sham injection plus focal/grid laser treatment, and 322 were randomly assigned to receive ranibizumab plus deferred or prompt focal/grid laser treatment. MAIN OUTCOMES AND MEASURES The cumulative probability of sustained IOP elevation, defined as IOP of at least 22 mm Hg and an increase of at least 6 mm Hg from baseline at 2 consecutive visits, or the initiation or augmentation of ocular hypotensive therapy, through 3 years of follow-up. RESULTS The mean (SD) baseline IOP in both treatment groups was 16 (3) mm Hg (range, 5-24 mm Hg). The cumulative probability of sustained IOP elevation or of initiation or augmentation of ocular hypotensive therapy by 3 years, after repeated ranibizumab injections, was 9.5% for the participants who received ranibizumab plus prompt or deferred focal/grid laser treatment vs 3.4% for the participants who received a sham injection plus focal/grid laser treatment (difference, 6.1% [99% CI, -0.2% to 12.3%]; hazard ratio, 2.9 [99% CI, 1.0-7.9]; P = .01). The distribution of IOP and the change in IOP from baseline at each visit through 3 years were similar in each group. CONCLUSIONS AND RELEVANCE In eyes with center-involved diabetic macular edema and no prior open-angle glaucoma, repeated intravitreous injections of ranibizumab may increase the risk of sustained IOP elevation or the need for ocular hypotensive treatment. Clinicians should be aware of this risk and should consider this information when following up with patients who have received intravitreous injections of anti-vascular endothelial growth factor for the treatment of diabetic macular edema.