Macular Atrophy in the HARBOR Study for Neovascular Age-Related Macular Degeneration Ophthalmology (IF 8.204) Pub Date : 2018-02-21 SriniVas R. Sadda, Lisa L. Tuomi, Beiying Ding, Anne E. Fung, J. Jill Hopkins
Purpose To evaluate macular atrophy (MA) presence in the 24-month HARBOR study (NCT00891735) for neovascular age-related macular degeneration (AMD). Design Post hoc analysis of a phase 3 multicenter, prospective, randomized, double-masked, active treatment–controlled clinical trial. Participants Evaluable subjects (N = 1095) with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD treated with ranibizumab 0.5 mg or 2.0 mg monthly or pro re nata (PRN). Methods Fluorescein angiograms (FAs) and color fundus photographs at baseline and months 3, 12, and 24 were retrospectively graded by masked graders for MA: well-defined areas of depigmentation with increased choroidal vessel visibility, diameter ≥250 μm, corresponding to flat areas of well-demarcated staining on FA, excluding atrophy associated with retinal pigment epithelium tears. Atrophy immediately within, adjacent, and nonadjacent to CNV lesions was included. Main Outcome Measures Macular atrophy incidence, best-corrected visual acuity (BCVA). Results At baseline, MA was detected in 11.2% (123/1095) of study eyes. At month 24, 29.4% (229/778) of eyes without baseline atrophy had detectable MA. Eyes with and without baseline MA had significant mean BCVA gains from baseline at month 24 (letters [95% confidence interval]: +6.7 [4.1–9.3]; +9.1 [8.0–10.2], respectively). Among eyes with and without MA at month 24, mean month 24 BCVA was 62.0 [60.3–63.7] and 64.7 [63.2–66.3] letters, respectively. Baseline risk factors for month 24 MA presence included intraretinal cysts (hazard ratio [HR], 2.45 [1.76–3.42]) and fellow eye atrophy (HR, 2.02 [1.42–2.87]); subretinal fluid was associated with a lower MA risk (HR, 0.50 [0.33–0.74]). Ranibizumab dose was not associated with MA development. Monthly versus PRN treatment trended toward an association with MA (HR, 1.29 [0.99–1.68]), but was not statistically significant. Conclusions New MA was detected in 29% of study eyes after 24 months of treatment. Clinically significant BCVA gains were achieved with MA present over 24 months. Baseline subretinal fluid absence, intraretinal cyst presence, and fellow eye atrophy presence were associated with month 24 MA presence. With existing data, the benefits of ranibizumab for neovascular AMD outweighed the risk of MA development over 24 months in HARBOR, although outcomes >2 years were not evaluated.
Characterizing Anterior Segment OCT Angle Landmarks of the Trabecular Meshwork Complex Ophthalmology (IF 8.204) Pub Date : 2018-02-21 Eric L. Crowell, Laura Baker, Alice Z. Chuang, Robert M. Feldman, Nicholas P. Bell, Patricia Chévez-Barrios, Lauren S. Blieden
Purpose To identify the presence or absence of 3 identifiable landmarks: trabecular meshwork (TM), Schlemm's canal (SC), and a novel landmark termed the band of extracanalicular limbal lamina (BELL), which is a landmark adjacent to SC visible on anterior segment (AS) OCT. These landmarks also were analyzed pathologically to identify all 3 landmarks. Design Retrospective review. Participants One eye per participant from prior institutional review board-approved studies in which AS OCT imaging was performed. Methods Horizontal images from 2-dimensional angle analysis scans using a CASIA SS-1000 (Tomey, Nagoya, Japan) AS OCT were evaluated by masked readers. Logistic regression was used to analyze the potential factors of age, gender, race, intraocular pressure, gonioscopy grade, angle location, and history or presence of surgery on the visibility of these structures. Pathologic correlation on 5 previously enucleated eyes also was performed. Main Outcome Measures Presence or absence of angle landmarks—TM, SC, and BELL—using Anterior Chamber Analysis and Interpretation software (ACAI, Houston, TX). Results Three hundred three angles of 153 horizontal images were included in this study. The mean age was 51.5±16.0 years, with 98 women (64%) and 100 white persons (66%). The outer border of the BELL was observed in 288 angles (95%), TM was found in 220 angles (73%), and SC was seen in 120 angles (40%). The outer border of the BELL was more visible in white persons (P = 0.02) than Asians and in eyes with a Spaeth gonioscopy grade of E than those with a grade of A (P = 0.02). Both TM (P = 0.001) and SC (P = 0.001) were more visible in temporal angles (81% for TM, 49% for SC) than in nasal angles (64% for TM, 30% for SC). Additionally, SC was more visible in open angles (43%) than in narrow angles (27%; P = 0.02). These 3 structures were verified in a pathologic study. Conclusions We identified a novel AS OCT landmark adjacent to SC. This structure also was identified on pathologic samples from enucleated eyes. Further study is needed to determine the pathophysiologic relevance of these findings.
Treatment Outcomes in the Primary Tube Versus Trabeculectomy Study after 1 Year of Follow-up Ophthalmology (IF 8.204) Pub Date : 2018-02-21
Purpose To report 1-year treatment outcomes in the Primary Tube Versus Trabeculectomy (PTVT) Study. Design Multicenter, randomized clinical trial. Participants Two hundred forty-two eyes of 242 patients with medically uncontrolled glaucoma and no previous incisional ocular surgery, including 125 in the tube group and 117 in the trabeculectomy group. Methods Patients were enrolled at 16 clinical centers and assigned randomly to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (MMC; 0.4 mg/ml for 2 minutes). Main Outcome Measures Intraocular pressure (IOP), glaucoma medical therapy, visual acuity, visual fields, surgical complications, and failure (IOP of more than 21 mmHg or reduced by less than 20% from baseline, IOP of 5 mmHg or less, reoperation for glaucoma, or loss of light perception vision). Results The cumulative probability of failure during the first year of follow-up was 17.3% in the tube group and 7.9% in the trabeculectomy group (P = 0.01; hazard ratio, 2.59; 95% confidence interval, 1.20–5.60). Mean ± standard deviation IOP was 13.8±4.1 mmHg in the tube group and 12.4±4.4 mmHg in the trabeculectomy group at 1 year (P = 0.01), and the number of glaucoma medications was 2.1±1.4 in the tube group and 0.9±1.4 in the trabeculectomy group (P < 0.001). Postoperative complications developed in 36 patients (29%) in the tube group and 48 patients (41%) in the trabeculectomy group (P = 0.06). Serious complications requiring reoperation or producing a loss of 2 Snellen lines or more occurred in 1 patient (1%) in the tube group and 8 patients (7%) in the trabeculectomy group (P = 0.03). Conclusions Trabeculectomy with MMC had a higher surgical success rate than tube shunt implantation after 1 year in the PTVT Study. Lower IOP with use of fewer glaucoma medications was achieved after trabeculectomy with MMC compared with tube shunt surgery during the first year of follow-up. The frequency of serious complications producing vision loss or requiring reoperation was lower after tube shunt surgery relative to trabeculectomy with MMC.
Vision-Related Quality of Life Associated with Unilateral and Bilateral Ocular Conditions Ophthalmology (IF 8.204) Pub Date : 2018-02-21
Purpose To present ophthalmic patient time-tradeoff vision utilities for quantifying vision-related quality-of-life when the fellow eye still has good vision. These utilities are important for performing reliable cost-utility analyses. Design Consecutive time-tradeoff vision utilities were obtained from ophthalmic patients with good vision (20/20–20/25) in one eye and vision ranging from 20/20 to no light perception in the fellow eye over a 15-year period from 2000 through 2014. Participants Five hundred eighty-six ophthalmic participant interviews from Wills Eye Hospital, New York Eye and Ear Hospital, and ophthalmology office practices in Pennsylvania and New Jersey. Methods Participants underwent a full ophthalmic examination, after which time-tradeoff vision utilities were obtained by personal interview by the authors using a standardized, validated instrument. Main Outcome Measures Time-tradeoff vision utilities. Results Mean time-tradeoff vision utilities were as follows in participants with good vision (20/20–20/25) in at least one eye and the following visions in the fellow eyes: no light perception, 0.79; counting fingers to light perception, 0.87; 20/200 to 20/400, 0.88; 20/60 to 20/100, 0.88; 20/30 to 20/50, 0.87; and 20/20 to 20/25, 0.94. Conclusions In people with good vision (20/20–20/25) in one eye, the associated mean time-tradeoff vision utility is a remarkably consistent 0.87 to 0.88 when vision in the fellow eye ranges from 20/30 to light perception. Vision of 20/20 to 20/25 in the fellow eye results in a significantly higher associated utility of 0.94 (P < 0.01), whereas vision of no light perception in the fellow eye results in a significantly lower utility of 0.079 (P < 0.01). These utilities are important for calculating reliable patient value (quality-adjusted life-year) gains in ophthalmic cost-utility analysis populations in which there is unilateral and bilateral disease involvement.
Endophthalmitis after Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors : Management and Visual Outcomes Ophthalmology (IF 8.204) Pub Date : 2018-02-21 Kunyong Xu, Eric K. Chin, Steven R. Bennett, David F. Williams, Edwin H. Ryan, Sundeep Dev, Robert A. Mittra, Polly A. Quiram, John B. Davies, D. Wilkin Parke III, Jill B. Johnson, Herbert L. Cantrill, David R.P. Almeida
Purpose We describe the presentation of patients developing endophthalmitis after intravitreal injection with vascular endothelial growth factor (VEGF) inhibitors. Moreover, we evaluate the management by comparing the outcomes of immediate tap and injection of intravitreal antibiotics (TAI) versus initial surgical pars plana vitrectomy (PPV). Finally, we analyze the predictive factors of visual outcomes at 6-month follow-up. Design Retrospective, single-center, nonrandomized interventional study. Participants Patients developing endophthalmitis after receiving an intravitreal injection of anti-VEGF agent between 2006 and 2016. Methods All patients received a vitreous biopsy sent for cultures before the initiation of treatment: TAI group versus PPV with intravitreal antibiotics (PPV group). Main Outcome Measures Best-corrected visual acuity (BCVA) at 6-month follow-up after treatment for endophthalmitis. Results A total of 258 357 intravitreal injections occurred over the course of the 10-year period, of which 40 patients (0.016%) had endophthalmitis within 3 weeks after injection. In total, 34 patients (85.0%) had pain and 25 patients (62.5%) had hypopyon on initial examination. Among 24 culture-positive cases, 66.7% of the causative organisms were coagulase-negative Staphylococcus, followed by Streptococcus species (10.0%). The best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution [logMAR]) at 6-month follow-up was significantly worse for patients who had a positive culture for Streptococcus species (4.0; standard deviation [SD], 0.8) (approximately light perception) compared with those who had a positive culture for coagulase-negative Staphylococcus (0.4; SD, 0.3) (∼20/50) (P < 0.0001). Compared with the TAI group, a higher proportion of samples were culture-positive in the PPV group (90.9% vs. 48.3%, P = 0.03). There was no statistically significant difference in BCVA at 6-month follow-up between the TAI and PPV groups. Younger age (<85 years) and lower intraocular pressure (IOP) at presentation were predictive of achieving a BCVA of 20/400 or better at 6-month follow-up after treatment. Initial management (TAI vs. PPV), duration of symptoms, presence of pain, presence of hypopyon, presenting BCVA, and culture status (positive vs. negative) were not found to be predictive of visual outcomes at 6-month follow-up. Conclusions No significant difference in BCVA at 6-month follow-up was detected between the TAI and PPV groups. Younger age and lower IOP at presentation were associated with better visual outcomes at 6-month follow-up.
Interocular Axial Length and Corneal Power Differences as Predictors of Postoperative Refractive Outcomes after Cataract Surgery Ophthalmology (IF 8.204) Pub Date : 2018-02-16 Vinay Kansal, Matthew Schlenker, Iqbal Ike K. Ahmed
Purpose To determine whether differences between eyes in axial length (AL) and corneal power (K) on optical biometry are predictive of refractive outcomes. Design Retrospective cohort study. Participants A total of 729 patients (1458 eyes) who underwent bilateral phacoemulsification at TLC (Mississauga, Ontario, Canada) from September 2013 to August 2015. Methods We compared the proportion of patients having >0.5 diopters (D) of refractive error from target stratified by interocular axial length differences (IALDs) and interocular K differences (IKDs) between eyes as measured by optical biometry (IOL-Master, Carl Zeiss Meditec, Oberkochen, Germany). Analysis was repeated for 0.25 D or 1.0 D targets and for patients with uncorrected visual acuity (UCVA) >0.3 logarithm of the minimum angle of resolution (logMAR) postoperatively. Main Outcome Measures Proportions, odds ratios (ORs), and corresponding 95% confidence intervals (CIs) were computed using generalized estimating equations to account for within-patient correlation. Results Some 79.1% of eyes were ≤0.5 D of refractive target, 47.0% were ≤0.25 D, and 97.2% were ≤1.0 D. The OR of having a refractive outcome >0.5 D from target for IALD cutoff of 0.2 mm was 1.4 (1.1–1.8), of 0.3 mm was 1.6 (1.2–2.1), and of 0.4 mm was 1.8 (1.3–2.5). This translates to 70.0% (63.5–75.7) within target for IALD of ≥0.4 mm versus 80.7% (78.4–82.9) for <0.4 mm. For a given patient with IALD, the chance of being off target was similar for the shorter and longer eye. Eyes outside of target were twice as likely to be <−0.5 D than >0.5 D. Interocular K difference was largely not associated with prediction error, yet larger IKD-flat, steep, and average were associated with increased odds of UCVA >0.3 logMAR postoperatively. Conclusions Interocular axial length difference of as little as ≥0.2 mm is associated with a higher chance of >0.5 D of refractive error from target and worse UCVA. Interocular K difference was not associated with worse refractive error from target, although a difference of ≥0.4 D was associated with worse UCVA. These cutoffs should be considered in preoperative planning and discussion with patients. Future study is required to assess whether repeating measurements, using adjunctive measurement devices, or attempting to separate true differences from artifact based on preoperative refractive characteristics reduces residual refractive error.
Dexamethasone Inserts in Noninfectious Uveitis : A Single-Center Experience Ophthalmology (IF 8.204) Pub Date : 2018-02-16 Dominika Pohlmann, Gerrit A. vom Brocke, Sibylle Winterhalter, Theresa Steurer, Sabrina Thees, Uwe Pleyer
Purpose To report the effectiveness of repeated intravitreal dexamethasone (DEX) inserts in noninfectious uveitis patients. Design Prospective, single-center, interventional clinical trial between February 2010 and March 2015. Participants Patients with noninfectious uveitis with cystoid macular edema and/or vitreitis. Methods Patients were treated with a 700-μg intravitreal DEX insert (Ozurdex; Allergan, Inc., Irvine, CA). Follow-up visits were scheduled 1, 3, and 6 months after injection. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), vitreous haze (VH) score, intraocular pressure (IOP), and adverse events were recorded. Main Outcome Measures Primary outcome was the reduction of CRT. Secondary outcome was the improvement in BCVA and reduction of VH. Results In total, 109 eyes of 76 patients received 298 DEX inserts. Fifty-two patients were women (68%). The mean age of all participants was 57 years (range, 24–88 years). More than 3 DEX inserts were injected into 44% of eyes. Mean number of injections were 1.54±0.5 (standard deviation [SD]), 1.98±0.84, and 2.46±1.1 over 12, 18, and 24 months, respectively. Central retinal thickness decreased significantly (P < 0.001) from 465 μm at baseline to 318, 342, and 388 μm after 1, 3, and 6 months, respectively. Similar trends were seen in eyes receiving a second, third, and fourth DEX insert. Patients with idiopathic uveitis and sarcoidosis benefited well from DEX inserts. The greatest overall benefit was achieved in patients with no systemic treatment and patients receiving antimetabolites and cyclosporin A. A significant VH score reduction was documented in 44% of eyes after 1 month. A gain of more than 3 lines in BCVA was recorded in 31% to 37%, 26% to 39%, and 8% to 32% of eyes after 1, 3, and 6 months, respectively. A transient rise in mean IOP after 1 month (P < 0.001) and after 3 months (P = 0.001) was seen. Conclusions The repeated longer-term administration of DEX inserts in noninfectious uveitis patients, either alone or in combination with other therapies, led to improved CRT, BCVA, and VH. Underlying diseases and concomitant systemic therapy seem to have an impact on overall treatment benefit. Ocular complications were reversible and were managed by local treatment, with exception of cataract formation.
Influence of Meibomian Gland Dysfunction and Friction-Related Disease on the Severity of Dry Eye Ophthalmology (IF 8.204) Pub Date : 2018-02-16 Chi Hoang Viet Vu, Motoko Kawashima, Masakazu Yamada, Kazuhisa Suwaki, Miki Uchino, Chika Shigeyasu, Yoshimune Hiratsuka, Norihiko Yokoi, Kazuo Tsubota
Purpose To evaluate the effect of meibomian gland dysfunction (MGD) and friction-related disease (FRD) on the severity of dry eye disease (DED). Design Cross-sectional observational study. Participants This study enrolled 449 patients with DED (63 men and 386 women; mean age, 62.6±15.7 years [range, 21–90 years]) for analysis. Methods Subjective symptoms, the ocular surface, tear function, and the presence of MGD and FRD (superior limbic keratoconjunctivitis, conjunctivochalasis, and lid wiper epitheliopathy) were investigated. Main Outcome Measures Schirmer value, tear film breakup time (TBUT), and keratoconjunctival score. Results We classified the participants into aqueous-deficient dry eye (ADDE; n = 231 [51.4%]) and short TBUT dry eye subtype (TBUT-DE; n = 109 [24.3%]) subgroups. The TBUT was shorter in patients with MGD than in those without MGD, whereas other ocular signs showed no difference (TBUT: MGD present, 1.97±1.02 seconds; MGD absent, 2.94±1.63 seconds [P < 0.001]; ADDE/MGD present, 1.94±1.08 seconds; ADDE/MGD absent, 2.77±1.61 seconds [P < 0.001]; short TBUT-DE/MGD present, 2.07±0.97 seconds; short TBUT-DE/MGD absent, 2.94±1.23 seconds [P = 0.01]). The ADDE patients with FRD showed a worse TBUT than ADDE patients without FRD (TBUT: ADDE/FRD present, 2.08±1.39 seconds; ADDE/FRD absent, 2.92±1.54 seconds; P < 0.001). Conclusions This study showed associations between MGD, FRD, or both and ocular signs in DED. In the presence of MGD, FRD, or both, TBUT was significantly shortened regardless of the dry eye status or subtype.
Return to the Operating Room after Macular Surgery : IRIS Registry Analysis Ophthalmology (IF 8.204) Pub Date : 2018-02-14 D. Wilkin Parke III, Flora Lum
Purpose To investigate the rate of return to the operating room after vitrectomy surgery to treat macular hole or epiretinal membrane. Design A retrospective registry cohort. Participants Individuals receiving care in ophthalmology practices participating in the Academy IRIS (Intelligent Research in Sight) Registry. Methods Data from the IRIS Registry were analyzed for patients who underwent vitrectomy for macular holes or epiretinal membranes. Cases were identified by the combination of International Classification of Diseases, 9th revision code (362.54, 362.56) and a current procedural terminology (CPT) code for vitrectomy surgery between January 1, 2013 and June 30, 2017. Main Outcome Measures The eyes that underwent additional eye surgery within 1 year after initial vitrectomy for macular hole or epiretinal membrane were identified, as was the nature of the additional procedures per CPT code. Results A total of 41 475 eyes underwent vitrectomy for macular hole and 73 219 eyes underwent vitrectomy for epiretinal membrane during the study period. In the macular hole group, 7573 had a second surgery within 1 year, and 2827 (6.8%) had a second surgery that was not cataract related. In the epiretinal membrane group, 12 433 had a second surgery within 1 year, 4022 (5.5%) of which were not cataract related. In the macular hole group, 4.6% of eyes returned to the operating room for another macular hole repair surgery, and 2.0% returned for retinal detachment repair. In the epiretinal membrane group, 1.4% returned for a second vitrectomy with membrane stripping, and 2.5% returned for retinal detachment repair. Conclusions This registry-based study encompassed a large number of patients but was limited by the inaccessibility of some information and the potential for inaccurate medical records or coding, as it obtained data from multiple electronic health records entities. Excluding cataract surgery, approximately 6% of eyes that underwent vitrectomy to address macular hole or epiretinal membrane returned for a second ophthalmic procedure within a year. In the macular hole group, most secondary non-cataract surgeries were for another macular hole repair procedure. For both macular holes and epiretinal membranes, approximately 2% of eyes required retinal detachment repair surgery within 1 year.
Predicting Visual Acuity by Using Machine Learning in Patients Treated for Neovascular Age-Related Macular Degeneration Ophthalmology (IF 8.204) Pub Date : 2018-02-14 Markus Rohm, Volker Tresp, Michael Müller, Christoph Kern, Ilja Manakov, Maximilian Weiss, Dawn A. Sim, Siegfried Priglinger, Pearse A. Keane, Karsten Kortuem
Purpose To predict, by using machine learning, visual acuity (VA) at 3 and 12 months in patients with neovascular age-related macular degeneration (AMD) after initial upload of 3 anti–vascular endothelial growth factor (VEGF) injections. Design Database study. Participants For the 3-month VA forecast, 653 patients (379 female) with 738 eyes and an average age of 74.1 years were included. The baseline VA before the first injection was 0.54 logarithm of the minimum angle of resolution (logMAR) (±0.39). A total of 456 of these patients (270 female, 508 eyes, average age: 74.2 years) had sufficient follow-up data to be included for a 12-month VA prediction. The baseline VA before the first injection was 0.56 logMAR (±0.42). Methods Five different machine-learning algorithms (AdaBoost.R2, Gradient Boosting, Random Forests, Extremely Randomized Trees, and Lasso) were used to predict VA in patients with neovascular AMD after treatment with 3 anti-VEGF injections. Clinical data features came from a data warehouse (DW) containing electronic medical records (41 features, e.g., VA) and measurement features from OCT (124 features, e.g., central retinal thickness). The VA of patient eyes excluded from machine learning was predicted and compared with the ground truth, namely, the actual VA of these patients as recorded in the DW. Main Outcome Measures Difference in logMAR VA after 3 and 12 months upload phase between prediction and ground truth as defined. Results For the 3-month VA forecast, the difference between the prediction and ground truth was between 0.11 logMAR (5.5 letters) mean absolute error (MAE)/0.14 logMAR (7 letters) root mean square error (RMSE) and 0.18 logMAR (9 letters) MAE/0.2 logMAR (10 letters) RMSE. For the 12-month VA forecast, the difference between the prediction and ground truth was between 0.16 logMAR (8 letters) MAE/0.2 logMAR (10 letters) RMSE and 0.22 logMAR (11 letters) MAE/0.26 logMAR (13 letters) RMSE. The best performing algorithm was the Lasso protocol. Conclusions Machine learning allowed VA to be predicted for 3 months with a comparable result to VA measurement reliability. For a forecast after 12 months of therapy, VA prediction may help to encourage patients adhering to intravitreal therapy.
Development and Course of Scars in the Comparison of Age-related Macular Degeneration Treatments Trials Ophthalmology (IF 8.204) Pub Date : 2018-02-14 Ebenezer Daniel, Wei Pan, Gui-shuang Ying, Benjamin J. Kim, Juan E. Grunwald, Frederick L. Ferris III, Glenn J. Jaffe, Cynthia A. Toth, Daniel F. Martin, Stuart L. Fine, Maureen G. Maguire
Purpose To describe risk factors for scar formation and changes to fibrotic scar through 5 years in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Design Multicenter, prospective cohort study. Participants A total of 1061 subjects in CATT. Methods Color photographic and fluorescein angiographic images from baseline and 1, 2, and 5 years were evaluated. Incidence of scar formation was estimated with Kaplan–Meier curves. Risk factors were assessed with Cox regression models. Main Outcome Measures Scar formation, fibrotic scar area, and macular atrophy associated with fibrotic scar (“atrophy”). Results Cumulative proportion of eyes with scar was 32%, 46%, and 56% at years 1, 2, and 5, respectively. Baseline factors associated with increased risk (adjusted hazards ratio [aHR] and 95% confidence interval [CI]) were classic choroidal neovascularization (CNV) (aHR, 4.49; 95% CI, 3.34–6.04) versus occult, hemorrhage >1 disc area (DA) (aHR, 2.28; 95% CI, 1.49–3.47) versus no hemorrhage, retinal thickness >212 μm (aHR, 2.58; 95% CI, 1.69–3.94) versus <120 μm, subretinal tissue complex thickness >275 μm (aHR, 2.64; 95% CI, 1.81–3.84) versus ≤75 μm, subretinal fluid thickness >25 μm (aHR, 1.31; 95% CI, 0.97–1.75) versus no fluid, visual acuity (VA) in fellow eye 20/20 (aHR, 1.72; 95% CI, 1.25–2.36) versus 20/50 or worse, retinal pigment epithelium elevation absence (aHR, 1.71; 95% CI, 1.21–2.41), and subretinal hyperreflective material (aHR, 1.72; 95% CI, 1.25–2.36). Among 68 eyes that developed fibrotic scar at year 1, VA decreased by a mean of additional 13 letters between years 1 and 5. Mean scar area was 1.2, 1.2, and 1.9 DA at 1, 2, and 5 years, respectively. Atrophy was present in 18%, 24%, and 54% of these eyes at years 1, 2, and 5, respectively; the mean areas were 1.6, 2.0, and 3.1 DA, respectively. Atrophy replaced fibrotic scar in 8 eyes at year 5. There was no significant correlation between scar growth and atrophy growth. The rate of growth for both was similar between the clinical trial and observation periods. Conclusions Several morphologic features, including classic CNV and large hemorrhage, are associated with scar formation. Rate of new scar formation declined after 2 years. Most fibrotic scars and accompanying macular atrophy expanded over time, reducing VA.
Dexamethasone Intracameral Drug-Delivery Suspension for Inflammation Associated with Cataract Surgery : A Randomized, Placebo-Controlled, Phase III Trial Ophthalmology (IF 8.204) Pub Date : 2018-02-13 Eric Donnenfeld, Edward Holland
Purpose To evaluate the safety and efficacy of an anterior chamber intracameral dexamethasone drug-delivery suspension (IBI-10090; DEXYCU; Icon Bioscience Inc., Newark, CA) that provides medication for up to 21 days with a single application in treating postoperative inflammation in patients undergoing cataract surgery. Design Prospective, randomized, double-masked, multicenter trial. Participants Patients with preoperative best-corrected visual acuity of 20/30 to 20/200 undergoing unilateral cataract surgery by phacoemulsification were randomized to receive IBI-10090 or placebo. Methods Three hundred ninety-four patients were randomized 1:2:2 to receive 5-μl injections of placebo or 5-μl injections of 342 or 517 μg IBI-10090 dexamethasone drug delivery suspension injected into the anterior chamber at the conclusion of cataract surgery. Patients were followed for 90 days after surgery. Main Outcome Measures Primary outcome was anterior chamber cell (ACC) clearing (ACC score of 0) in the study eye at postoperative day (POD) 8. Secondary outcome measures were anterior chamber flare and ACC plus flare clearing in the study eye. Ocular and nonocular adverse events were assessed. Results Anterior chamber cell clearing at POD 8 was achieved in 25.0% of eyes in the placebo group and in 63.1% and 66.0% of eyes in the 342- and 517-μg treatment groups, respectively (P < 0.001). Anterior chamber flare clearing at POD 8 was achieved by 63.8% of eyes in the placebo group and in 92.4% and 89.1% of eyes in the 342- and 517-μg IBI-10090 treatment groups, respectively (P < 0.001). Anterior chamber cell plus flare clearing at POD 8 was achieved in 33.8% of eyes receiving placebo and in 63.1% and 67.3% of eyes receiving 342- and 517-μg IBI-10090, respectively (P < 0.001). Adverse events among the 3 groups were similar, and no serious ocular adverse events were reported up to POD 90. Conclusions The IBI-10090 dexamethasone drug-delivery suspension placed in the anterior chamber after cataract surgery at concentrations of 342 and 517 μg was safe and effective in treating inflammation occurring after cataract surgery and may be an alternative to corticosteroid drop installation in this patient population.
Consistent Long-Term Therapy of Neovascular Age-Related Macular Degeneration Managed by 50 or More Anti–VEGF Injections Using a Treat-Extend-Stop Protocol Ophthalmology (IF 8.204) Pub Date : 2018-02-10 Sean D. Adrean, Siyang Chaili, Hema Ramkumar, Ash Pirouz, Scott Grant
PurposeTo examine the clinical results for patients with neovascular age-related macular degeneration (nAMD) who were managed with a treat-extend-stop (TES) protocol and received 50 or more injections of anti–vascular endothelial growth factor (VEGF) agents.DesignRetrospective case study.ParticipantsData for patients from a private retina practice meeting the following criteria were included: diagnosis of nAMD and having received 50 or more intravitreal injections of anti-VEGF agents.MethodsThe patients' baseline visual acuity (VA; obtained using Snellen charts and converted to Early Treatment Diabetic Retinopathy Study [ETDRS] letters), age, length of follow-up, anti-VEGF agents used, and interval between treatments were obtained. These data were examined through the 51st injection and at the last follow-up examination. Patients were excluded if they lost significant vision because of a diagnosis unrelated to AMD during therapy.Main Outcome MeasuresVisual acuity and complications.ResultsSixty-seven eyes of 71 patients were identified who met inclusion criteria. The mean age of patients was 83.0 years. Women made up 58.2% of the study population, whereas men constituted 41.8%. The mean initial VA was 55.6 ETDRS letters. The mean duration of follow-up at the 51st visit for an injection was 6.4 years, and the mean duration of follow-up at the last visit was 8 years. The mean number of injections at final follow-up was 63.7. The mean interval between treatments at the 51st follow-up was 5.4 weeks, and the mean follow-up at the last examination was 6.4 weeks. Mean VA at the 51st injection was 65.3 letters, and the mean change from baseline was 9.7 letters (P < 0.001, Student paired t test). The mean vision gained at last follow-up was 8.7 letters from baseline (P < 0.001), or 64.3 letters.ConclusionsIn this study, patients gained a mean of 2 ETDRS lines after 50 injections. This study had a mean follow-up of 8 years, and 35.2% of eyes had a 3-line or more gain in VA at the last follow-up examination. Patients who require consistent long-term anti-VEGF therapy, managed with a TES protocol, are likely able to maintain or improve their vision.
Systemic Medication Associations with Presumed Advanced or Uncontrolled Primary Open-Angle Glaucoma Ophthalmology (IF 8.204) Pub Date : 2018-02-09 Wei Zheng, Thaddeus P. Dryja, Zhongyuan Wei, Dongying Song, Haijun Tian, Kristijan H. Kahler, Anthony P. Khawaja
Integrating Macular Ganglion Cell Inner Plexiform Layer and Parapapillary Retinal Nerve Fiber Layer Measurements to Detect Glaucoma Progression Ophthalmology (IF 8.204) Pub Date : 2018-02-09 Hei Wan Hou, Chen Lin, Christopher Kai-Shun Leung
Purpose To investigate the temporal relationship among progressive macular ganglion cell inner plexiform layer (GCIPL) thinning, progressive parapapillary retinal nerve fiber layer (RNFL) thinning, and visual field (VF) progression in patients with primary open-angle glaucoma (POAG). Design Prospective study. Participants One hundred thirty-six POAG patients (231 eyes) followed up for ≥5 years. Methods OCT imaging of the macular GCIPL and parapapillary RNFL and perimetry were performed at ∼ 4-month intervals. Progressive GCIPL and RNFL thinning were determined by Guided Progression Analysis (GPA) of serial GCIPL and RNFL thickness maps. The specificities of GPA were calculated from the proportions of eyes with progressive GCIPL or RNFL thinning in 67 eyes of 36 healthy individuals followed up for ≥5 years. Visual field progression (likely or possible) was determined by the Early Manifest Glaucoma Trial criteria. Main Outcome Measures Hazard ratios for VF progression, progressive RNFL thinning, and progressive GCIPL thinning, as determined by time-varying Cox models. Results GPA detected 57 eyes (24.7%) with progressive GCIPL thinning and 66 eyes (28.6%) with progressive RNFL thinning at a specificity of 95.5% and 91.0%, respectively. Thirty-five eyes (15.2%) demonstrated progressive RNFL and GCIPL thinning, whereas 53 eyes (22.9%) demonstrated progressive RNFL or GCIPL thinning. Eyes with progressive GCIPL thinning had a higher risk for progressive RNFL thinning (HR, 5.27; 95% confidence interval [CI], 2.89–9.62), whereas eyes with progressive RNFL thinning were also at a higher risk for progressive GCIPL thinning (HR, 2.99; 95% CI, 1.48–6.02), after adjusting for baseline covariates. The HRs for likely and possible VF progression were 3.48 (95% CI, 1.51–8.01) and 2.74 (95% CI, 1.26–5.98), respectively, on detection of progressive GCIPL thinning and 3.66 (95% CI, 1.68–7.97) and 2.54 (95% CI, 1.23–5.21), respectively, on detection of progressive RNFL thinning after adjusting for baseline covariates. Eyes with VF progression were not at risk of progressive RNFL or GCIPL thinning (P ≥ 0.493). Conclusions Progressive macular GCIPL thinning and progressive parapapillary RNFL thinning are mutually predictive. Because progressive RNFL thinning and progressive GCIPL thinning are both indicative of VF progression, integrating macular GCIPL and parapapillary RNFL measurements is relevant to facilitate early detection of disease deterioration in glaucoma patients.
Safety and Efficacy of Adalimumab in Patients with Noninfectious Uveitis in an Ongoing Open-Label Study: VISUAL III Ophthalmology (IF 8.204) Pub Date : 2018-02-09 Eric B. Suhler, Alfredo Adán, Antoine P. Brézin, Eric Fortin, Hiroshi Goto, Glenn J. Jaffe, Toshikatsu Kaburaki, Michal Kramer, Lyndell L. Lim, Cristina Muccioli, Quan Dong Nguyen, Joachim Van Calster, Luca Cimino, Martina Kron, Alexandra P. Song, Jianzhong Liu, Sophia Pathai, Anne Camez, Ariel Schlaen, Mirjam E.J. van Velthoven, Albert T. Vitale, Manfred Zierhut, Samir Tari, Andrew D. Dick
Purpose To evaluate safety and efficacy of adalimumab in patients with noninfectious intermediate, posterior, or panuveitis. Design Phase 3, open-label, multicenter clinical trial extension (VISUAL III). Participants Adults meeting treatment failure (TF) criteria or who completed VISUAL I or II (phase 3, randomized, double-masked, placebo-controlled) without TF. Methods Patients received adalimumab 40 mg every other week. Interim follow-up data were described from VISUAL III weeks 0 through 78. Main Outcome Measures Disease quiescence, steroid-free quiescence, active inflammatory chorioretinal/retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, best-corrected visual acuity (BCVA), and corticosteroid dose. Binary data were reported using nonresponder imputation (NRI), continuous data using last observation carried forward and as-observed analysis, and corticosteroid dose using observed-case analysis. Adverse events (AEs) were reported from first adalimumab dose in VISUAL III through interim cutoff. Results Of 424 patients enrolled, 371 were included in intent-to-treat analysis. At study entry, 242 of 371 (65%) patients had active uveitis; 60% (145/242, NRI) achieved quiescence at week 78, and 66% (95/143, as-observed) of those were corticosteroid free. At study entry, 129 of 371 (35%) patients had inactive uveitis; 74% (96/129, NRI) achieved quiescence at week 78, and 93% (89/96, as-observed) of those were corticosteroid free. Inflammatory lesions, anterior chamber grade, and vitreous haze grade showed initial improvement followed by decline in patients with active uveitis and remained stable in patients with inactive uveitis. BCVA improved in patients with active uveitis from weeks 0 to 78 (0.27 to 0.14 logMAR; left and right eyes; as-observed) and remained stable in patients with inactive uveitis. Mean corticosteroid dose decreased from 13.6 mg/day (week 0) to 2.6 mg/day (week 78) in patients with active uveitis and remained stable in those with inactive uveitis (1.5–1.2 mg/day). AEs (424 events/100 patient-years) and serious AEs (16.5 events/100 patient-years) were comparable with previous VISUAL trials. Conclusions Patients with active uveitis at study entry who received adalimumab therapy were likely to achieve quiescence, improve visual acuity, and reduce their daily uveitis-related systemic corticosteroid use. Most patients with inactive uveitis at study entry sustained quiescence without a systemic corticosteroid dose increase. No new safety signals were identified.
Leber Congenital Amaurosis Associated with Mutations in CEP290, Clinical Phenotype, and Natural History in Preparation for Trials of Novel Therapies Ophthalmology (IF 8.204) Pub Date : 2018-02-03 Leo Sheck, Wayne I.L. Davies, Phillip Moradi, Anthony G. Robson, Neruban Kumaran, Alki C. Liasis, Andrew R. Webster, Anthony T. Moore, Michel Michaelides
Purpose To investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children. Design Retrospective case series. Participants Patients with mutations in CEP290 identified at a single UK referral center. Methods Review of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing. Main Outcome Measures Molecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment. Results Forty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features. Conclusions Detailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches.
Conservatively Treated Orbital Blowout Fractures : Spontaneous Radiologic Improvement Ophthalmology (IF 8.204) Pub Date : 2018-02-03 Stephanie Ming Young, Yoon-Duck Kim, Sang Wook Kim, Han Byeol Jo, Stephanie S. Lang, Kyuyeon Cho, Kyung In Woo
Purpose To determine if conservatively treated blowout fractures of the orbit undergo spontaneous improvement based on radiologic findings. Design Prospective, noncomparative series. Participants Patients with conservatively treated orbital blowout fractures in a single tertiary institution from 2012 through 2016 with initial and follow-up computed tomography (CT) scans. Methods Comparison of initial and follow-up CT to assess for smoothening of bony contour, joining of bony edges, reduction in herniation of orbital contents, and new bone formation. Orbital and fracture volumes were calculated using a 3-dimensional reconstruction software program (3D Workstation; TeraRecon, Foster City, CA). Main Outcome Measures Change in bony contour, new bone formation, and decrease in orbital and fracture volumes. Results Our study comprised 41 patients and 44 orbits, with 38 unilateral and 3 bilateral cases. Most were men (65.9%; n = 27), and the mean age was 34.3±13.5 years. The mean time from injury to follow-up scan was 4.6 months. All orbits showed changes in bony contour from initial to follow up CT, including smoothening of the orbital contour (88.6%), joining of bony edges (90.9%), and reduction in herniation of orbital contents (65.9%). Most of the orbits (n = 41; 93.2%) showed features of neobone formation. Of the 44 orbits, 91.4% showed a decrease in orbital volume, whereas 94.3% showed a decrease in fracture volume. The reduction in volume was statistically significant for both orbital (from 23.7±4.0 to 21.8±3.9 ml) as well as fracture (from 1.2±0.8 to 0.7±0.6 ml) volumes from initial to follow-up scans, respectively (P < 0.001). Conclusions A large proportion of patients showed improvement in radiologic findings despite being treated conservatively. This highlights the spontaneous improvement that can occur in untreated blowout fractures not just clinically, but radiologically, in terms of soft tissue and bony findings.
Genome-Wide Association Study Reveals Variants in CFH and CFHR4 Associated with Systemic Complement Activation : Implications in Age-Related Macular Degeneration Ophthalmology (IF 8.204) Pub Date : 2018-02-02 Laura Lorés-Motta, Constantin C. Paun, Jordi Corominas, Marc Pauper, Maartje J. Geerlings, Lebriz Altay, Tina Schick, Mohamed R. Daha, Sascha Fauser, Carel B. Hoyng, Anneke I. den Hollander, Eiko K. de Jong
Purpose To identify genetic variants associated with complement activation, which may help to select age-related macular degeneration (AMD) patients for complement-inhibiting therapies. Design Genome-wide association study (GWAS) followed by replication and meta-analysis. Participants AMD patients and controls (n = 2245). Methods A GWAS on serum C3d-to-C3 ratio was performed in 1548 AMD patients and controls. For replication and meta-analysis, 697 additional individuals were genotyped. A model for complement activation including genetic and non-genetic factors was built, and the variance explained was estimated. Haplotype analysis was performed for 8 SNPs across the CFH/CFHR locus. Association with AMD was performed for the variants and haplotypes found to influence complement activation. Main Outcome Measures Normalized C3d/C3 ratio as a measure of systemic complement activation. Results Complement activation was associated independently with rs3753396 located in CFH (Pdiscovery = 1.09 × 10−15; Pmeta = 3.66 × 10−21; β = 0.141; standard error [SE] = 0.015) and rs6685931 located in CFHR4 (Pdiscovery = 8.18 × 10−7; Pmeta = 6.32 × 10−8; β = 0.054; SE = 0.010). A model including age, AMD disease status, body mass index, triglycerides, rs3753396, rs6685931, and previously identified SNPs explained 18.7% of the variability in complement activation. Haplotype analysis revealed 3 haplotypes (H1–2 and H6 containing rs6685931 and H3 containing rs3753396) associated with complement activation. Haplotypes H3 and H6 conferred stronger effects on complement activation compared with the single variants (P = 2.53 × 10−14; β = 0.183; SE = 0.024; and P = 4.28 × 10−4; β = 0.144; SE = 0.041; respectively). Association analyses with AMD revealed that SNP rs6685931 and haplotype H1–2 containing rs6685931 were associated with a risk for AMD development, whereas SNP rs3753396 and haplotypes H3 and H6 were not. Conclusions The SNP rs3753396 in CFH and SNP rs6685931 in CFHR4 are associated with systemic complement activation levels. The SNP rs6685931 in CFHR4 and its linked haplotype H1–2 also conferred a risk for AMD development, and therefore could be used to identify AMD patients who would benefit most from complement-inhibiting therapies.
Long-Term Outcomes of Total Exudative Retinal Detachments in Stage 3B Coats Disease Ophthalmology (IF 8.204) Pub Date : 2018-02-01 Albert S. Li, Antonio Capone Jr., Michael T. Trese, Jonathan E. Sears, Andres Kychenthal, Irina De la Huerta, Philip J. Ferrone
Purpose To evaluate the long-term outcomes of treatment of total exudative retinal detachments (ERDs) secondary to Coats disease (stage 3B) and the role of vitrectomy. Design Retrospective, observational case series. Participants A total of 16 eyes in 16 patients undergoing treatment for total ERDs secondary to Coats disease with at least 5 years of follow-up. Methods We reviewed the records of patients with stage 3B Coats disease. The interventions, including the timing of vitrectomy if used, and clinical course were recorded. Main Outcome Measures The primary outcome measures were visual acuity at the most recent appointment, whether there was progression to neovascular glaucoma (NVG) or phthisis bulbi, and need for enucleation. Results All patients received ablative treatment (photocoagulation or cryotherapy), with 8 having scleral buckling (SB) and 6 having external drainage of subretinal fluid (XD). Of the 12 patients who had pars plana vitrectomy (PPV), 8 had early PPV (EV) in the first year after presenting, and 4 of 8 in the expectant management group had late PPV (late vitrectomy) at a mean of 4.3 years post-presentation for treatment of significant traction retinal detachment (TRD). The other 4 patients of 8 in the expectant management group did not require vitrectomy. Mean follow-up overall was 9 1/2 years. At the date of last follow-up, 50% had no light perception or light perception vision, which was consistent across the subgroups that underwent EV (4/8), late vitrectomy (2/4), or no PPV (2/4). A total of 4 of 16 patients had progression to NVG or phthisis, 1 of whom required enucleation. Conclusions In this retrospective series of patients with Stage 3B Coats disease, ablative therapy with a combination of PPV, XD, or SB was effective in preventing progression to NVG or phthisis in the majority of patients, thus preserving the globe. Half of the patients (4/8) in this series who did not undergo PPV in the early vitrectomy group developed late-onset TRD, suggesting a possible role for early prophylactic vitrectomy with possible SB and XD; however, this is balanced by the other half (4/8) in the expectant management group who did not require any vitrectomy.
Characterizing Disease Burden and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration Ophthalmology (IF 8.204) Pub Date : 2018-02-01 Usha Chakravarthy, Clare C. Bailey, Robert L. Johnston, Martin McKibbin, Rehna S. Khan, Sajjad Mahmood, Louise Downey, Narendra Dhingra, Christopher Brand, Christopher J. Brittain, Jeffrey R. Willis, Sarah Rabhi, Anushini Muthutantri, Ronald A. Cantrell
Purpose To understand levels of disease burden and progression in a real-world setting among patients from the United Kingdom with bilateral geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Design Retrospective cohort analysis of a multicenter electronic medical record (EMR) database. Participants Patients who were aged ≥50 years with bilateral GA and no history of choroidal neovascularization (CNV) and who attended 1 of 10 clinical sites using the EMR. Methods A deidentified data set was constructed from the records held at the 10 sites. An algorithm was used to extract cases with a GA diagnosis, of which 1901 had bilateral GA and form the basis of this report. A sample of records randomly selected from each center was used to validate disease definitions. Main Outcome Measures Progression to blindness (visual acuity [VA] <20 letters or Snellen 3/60 in the better-seeing eye), driving ineligibility (VA ≤70 letters or Snellen 6/12 in the better-seeing eye), progression to CNV, loss of 10 or more letters, and mean change in VA over time. Results At first record of GA, 7.1% had a VA in the better-seeing eye equal to or lower than the cutoff for blindness registration and 71.1% had a VA that would have rendered them ineligible to drive. Over time, 16% became legally blind (median time to outcome, 6.2 years) and 66.7% became ineligible to drive (median time to outcome, 1.6 years). In the worse-seeing eye, 40.1% lost ≥10 letters in 2.4 years. Among patients with baseline and 24-month VA measurements, mean VA decline was 6.1 letters in the worse-seeing eye (n = 413) and 12.4 letters in the better-seeing eye (n = 414). The rate of progression to CNV in either eye was 7.4% per patient-year. Conclusions At initial diagnosis, based on VA in the better-seeing eye, a high proportion of patients with bilateral GA were ineligible to drive and approximately 7% were eligible for UK blindness registration. The subsequent reduction in VA that occurred in the better-seeing eye would render a further two-thirds ineligible to drive. These findings emphasize the severity of the visual disability associated with GA secondary to AMD.
Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study) Ophthalmology (IF 8.204) Pub Date : 2018-02-01 João Figueira, Emily Fletcher, Pascale Massin, Rufino Silva, Francesco Bandello, Edoardo Midena, Monica Varano, Sobha Sivaprasad, Haralabos Eleftheriadis, Geeta Menon, Miguel Amaro, Sarah Ayello Scheer, Catherine Creuzot-Garcher, João Nascimento, Dalila Alves, Sandrina Nunes, Conceição Lobo, José Cunha-Vaz
Purpose Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. Design Prospective, randomized, multicenter, open-label, phase II/III study. Participants Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). Methods Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion. Main Outcome Measures The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. Results Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported. Conclusions Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months.
Genetic Risk Score Is Associated with Vertical Cup-to-Disc Ratio and Improves Prediction of Primary Open-Angle Glaucoma in Latinos Ophthalmology (IF 8.204) Pub Date : 2018-02-01 Drew R. Nannini, Heejin Kim, Fangda Fan, Xiaoyi Gao
Purpose Genome-wide association studies have identified multiple genetic variants associated with vertical cup-to-disc ratio (VCDR). Genetic risk scores (GRS) examine the aggregate genetic effect of individual variants on a trait by combining these separate genetic variants into a single measure. The purpose of this study was to construct GRS for VCDR and to determine whether the GRS are associated with VCDR and whether the GRS increase the discriminatory ability for primary open-angle glaucoma (POAG) in a Latino population. Design Population-based genetic association study. Participants A total of 4018 Latino participants recruited from Los Angeles. Methods Weighted and unweighted GRS were constructed using 68 previously reported VCDR single nucleotide polymorphisms (SNPs), as well as SNPs from our own genome-wide association data. Linear and logistic regression analyses examined the associations of GRS with VCDR and POAG, respectively. To evaluate the discriminatory ability of the GRS for POAG, we conducted receiver operating characteristic (ROC) analyses. Main Outcome Measures The relationship between GRS and VCDR in Latinos. Results The GRS were associated significantly with VCDR (P < 0.0001), after adjusting for age, gender, central corneal thickness, intraocular pressure, and education. The weighted GRS explained an additional 2.74% of the variation in VCDR. Adding the weighted GRS derived from previously reported SNPs resulted in a moderate improvement in the discriminatory ability for POAG during ROC analyses, yielding an area under the ROC curve (AUC) of 0.735 (95% CI, 0.701–0.768). When our own SNPs were used, the AUC increased significantly to 0.809 (95% CI, 0.781–0.837; P < 0.0001). We obtained similar results for the unweighted GRS. Conclusions To our knowledge, we identified a novel association between GRS and VCDR and its improvement in the discriminatory ability of POAG in a Latino population.
The African Descent and Glaucoma Evaluation Study (ADAGES) III : Contribution of Genotype to Glaucoma Phenotype in African Americans: Study Design and Baseline Data Ophthalmology (IF 8.204) Pub Date : 2018-02-01 Linda M. Zangwill, Radha Ayyagari, Jeffrey M. Liebmann, Christopher A. Girkin, Robert Feldman, Harvey Dubiner, Keri A. Dirkes, Matthew Holmann, Eunice Williams-Steppe, Naama Hammel, Luke J. Saunders, Suzanne Vega, Kevin Sandow, Kathryn Roll, Rigby Slight, Daniel Auerbach, Brian C. Samuels, Joseph F. Panarelli, John P. Mitchell, Lama A. Al-Aswad, Sung Chul Park, Celso Tello, Jeremy Cotliar, Rajendra Bansal, Paul A. Sidoti, George A. Cioffi, Dana Blumberg, Robert Ritch, Nicholas P. Bell, Lauren S. Blieden, Garvin Davis, Felipe A. Medeiros, Maggie C.Y. Ng, Swapan K. Das, Nicholette D. Palmer, Jasmin Divers, Carl D. Langefeld, Barry I. Freedman, Donald W. Bowden, Mark A. Christopher, Yii-der I. Chen, Xiuqing Guo, Kent D. Taylor, Jerome I. Rotter, Robert N. Weinreb
Purpose To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III. Design Cross-sectional, case-control study. Participants Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States. Methods Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review. Main Outcome Measures Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded. Results The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients. Conclusions With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.
Efficacy and Safety of Ranibizumab 0.5 mg for the Treatment of Macular Edema Resulting from Uncommon Causes : Twelve-Month Findings from PROMETHEUS Ophthalmology (IF 8.204) Pub Date : 2018-01-20 Giovanni Staurenghi, Timothy Y.Y. Lai, Paul Mitchell, Sebastian Wolf, Andreas Wenzel, Jun Li, Amitabha Bhaumik, Philip G. Hykin
Purpose To evaluate the efficacy and safety of ranibizumab 0.5 mg in adult patients with macular edema (ME) resulting from any cause other than diabetes, retinal vein occlusion, or neovascular age-related macular degeneration. Design A phase 3, 12-month, double-masked, randomized, sham-controlled, multicenter study. Participants One hundred seventy-eight eligible patients aged ≥18 years. Methods Patients were randomized 2:1 to receive either ranibizumab 0.5 mg (n = 118) or sham (n = 60) at baseline and month 1. From month 2, patients in both arms received open-label individualized ranibizumab treatment based on disease activity. A preplanned subgroup analysis was conducted on the primary end point on 5 predefined baseline ME etiologies (inflammatory/post-uveitis, pseudophakic or aphakic, central serous chorioretinopathy, idiopathic, and miscellaneous). Main Outcome Measures Changes in best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study letters) from baseline to month 2 (primary end point) and month 12 and safety over 12 months. Results Overall, 156 patients (87.6%) completed the study. The baseline characteristics were well balanced between the treatment arms. Overall, ranibizumab showed superior efficacy versus sham from baseline to month 2 (least squares mean BCVA, +5.7 letters vs. +2.9 letters; 1-sided P = 0.0111), that is, a treatment effect (TE) of +2.8 letters. The mean BCVA gain from baseline to month 12 was 9.6 letters with ranibizumab. The TE at month 2 was variable in the 5 predefined etiology subgroups, ranging from >5-letter gain to 0.5-letter loss. The safety findings were consistent with the well-established safety profile of ranibizumab. Conclusions The primary end point was met and ranibizumab showed superiority in BCVA gain over sham in treating ME due to uncommon causes, with a TE of +2.8 letters versus sham at month 2. At month 12, the mean BCVA gain was high (9.6 letters) in the ranibizumab arm; however, the TE was observed to be variable across the different etiology subgroups, reaching a >1-line TE in BCVA in patients with ME resulting from inflammatory conditions/post-uveitis or after cataract surgery. Overall, ranibizumab was well tolerated with no new safety findings up to month 12.
Myopia Prevention and Outdoor Light Intensity in a School-Based Cluster Randomized Trial Ophthalmology (IF 8.204) Pub Date : 2018-01-19 Pei-Chang Wu, Chueh-Tan Chen, Ken-Kuo Lin, Chi-Chin Sun, Chien-Neng Kuo, Hsiu-Mei Huang, Yi-Chieh Poon, Meng-Ling Yang, Chau-Yin Chen, Jou-Chen Huang, Pei-Chen Wu, I-Hui Yang, Hun-Ju Yu, Po-Chiung Fang, Chia-Ling Tsai, Shu-Ti Chiou, Yi-Hsin Yang
Purpose To investigate the effectiveness of a school-based program promoting outdoor activities in Taiwan for myopia prevention and to identify protective light intensities. Design Multi-area, cluster-randomized intervention controlled trial. Participants A total 693 grade 1 schoolchildren in 16 schools participated. Two hundred sixty-seven schoolchildren were in the intervention group and 426 were in the control group. Methods Initially, 24 schools were randomized into the intervention and control groups, but 5 and 3 schools in the intervention and control groups, respectively, withdrew before enrollment. A school-based Recess Outside Classroom Trial was implemented in the intervention group, in which schoolchildren were encouraged to go outdoors for up to 11 hours weekly. Data collection included eye examinations, cycloplegic refraction, noncontact axial length measurements, light meter recorders, diary logs, and questionnaires. Main Outcome Measures Change in spherical equivalent and axial length after 1 year and the intensity and duration of outdoor light exposures. Results The intervention group showed significantly less myopic shift and axial elongation compared with the control group (0.35 diopter [D] vs. 0.47 D; 0.28 vs. 0.33 mm; P = 0.002 and P = 0.003) and a 54% lower risk of rapid myopia progression (odds ratio, 0.46; 95% confidence interval [CI], 0.28–0.77; P = 0.003). The myopic protective effects were significant in both nonmyopic and myopic children compared with controls. Regarding spending outdoor time of at least 11 hours weekly with exposure to 1000 lux or more of light, the intervention group had significantly more participants compared with the control group (49.79% vs. 22.73%; P < 0.001). Schoolchildren with longer outdoor time in school (≥200 minutes) showed significantly less myopic shift (measured by light meters; ≥1000 lux: 0.14 D; 95% CI, 0.02–0.27; P = 0.02; ≥3000 lux: 0.16 D; 95% CI, 0.002–0.32; P = 0.048). Conclusions The school-based outdoor promotion program effectively reduced the myopia change in both nonmyopic and myopic children. Outdoor activities with strong sunlight exposure may not be necessary for myopia prevention. Relatively lower outdoor light intensity activity with longer time outdoors, such as in hallways or under trees, also can be considered.
Genetic Background of Iris Melanomas and Iris Melanocytic Tumors of Uncertain Malignant Potential Ophthalmology (IF 8.204) Pub Date : 2018-01-19 Natasha M. van Poppelen, Jolanda Vaarwater, Hardeep S. Mudhar, Karen Sisley, Ian G. Rennie, Paul Rundle, Tom Brands, Quincy C.C. van den Bosch, Hanneke W. Mensink, Annelies de Klein, Emine Kiliç, Robert M. Verdijk
Purpose Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Iris melanoma comprises 4% to 10% of all UMs and has a lower mortality rate. The genetic changes in iris melanoma are not as well characterized as ciliary body or choroidal melanoma. The aim of this study was to gain more insight into the genetic background of iris melanoma and iris nevi. Design Multicenter, retrospective case series. Participants Patients diagnosed with iris melanoma or iris nevi who underwent surgical intervention as primary or secondary treatment. Methods Next-generation sequencing of GNAQ, GNA11, EIF1AX, SF3B1, BAP1, NRAS, BRAF, PTEN, c-Kit, TP53, and TERT was performed on 30 iris melanomas and 7 iris nevi. Copy number status was detected using single nucleotide polymorphisms (SNPs) included in the next-generation sequencing (NGS) panel, SNP array, or fluorescent in situ hybridization. BAP1 immunohistochemistry was performed on all samples. Main Outcome Measures Mutation and copy number status were analyzed. Results of BAP1 immunohistochemistry were used for survival analysis. Results In 26 of the 30 iris melanoma and all iris nevi, at least 1 mutation was identified. Multiple mutations were detected in 23 iris melanoma and 5 nevi, as well as mutations in GNAQ and GNA11. Furthermore, 13 of 30 BAP1, 5 of 30 EIF1AX, and 2 of 30 SF3B1 mutations were identified in iris melanoma. No correlation between BAP1 status and disease-free survival was found. The iris nevi showed 1 EIF1AX and 3 BAP1 mutations. Two of the nevi, with a BAP1 mutation, were histologically borderline malignant. Mutations in NRAS, BRAF, PTEN, c-KIT, and TP53 were detected in 6 iris melanomas and 4 iris nevi. Conclusions Mutations that are often found in uveal and cutaneous melanoma were identified in this cohort of iris melanomas and iris nevi. Therefore, iris melanomas harbor a molecular profile comparable to both choroidal melanoma and cutaneous melanoma. These findings may offer adjuvant targeted therapies for iris melanoma. There was no prognostic significance of BAP1 expression as seen in choroidal melanoma. Consequently, iris melanoma is a distinct molecular subgroup of UM. Histologic borderline malignant iris nevi can harbor BAP1 mutations and may be designated iris melanocytic tumors of uncertain malignant potential.
Progression of Myopic Maculopathy during 18-Year Follow-up Ophthalmology (IF 8.204) Pub Date : 2018-01-19 Yuxin Fang, Tae Yokoi, Natsuko Nagaoka, Kosei Shinohara, Yuka Onishi, Tomoka Ishida, Takeshi Yoshida, Xian Xu, Jost B. Jonas, Kyoko Ohno-Matsui
Purpose To examine the progression pattern of myopic maculopathy. Design Retrospective, observational case series. Participants Highly myopic patients who had been followed up for 10 years or more. Methods Using fundus photographs, myopic features were differentiated according to Meta-analysis of Pathologic Myopia (META-PM) Study Group recommendations. Main Outcome Measures Progression pattern of maculopathy. Results The study included 810 eyes of 432 patients (mean age, 42.3±16.8 years; mean axial length, 28.8±1.9 mm; mean follow-up, 18.7±7.1 years). The progression rate of myopic maculopathy was 47.0 per 1000 eye-years. Within the pathologic myopia (PM) group (n = 521 eyes), progression of myopic maculopathy was associated with female gender (odds ratio [OR], 2.21; P = 0.001), older age (OR, 1.03; P = 0.002), longer axial length (OR, 1.20; P = 0.007), greater axial elongation (OR, 1.45; P = 0.005), and development of parapapillary atrophy (PPA; OR, 3.14; P < 0.001). Diffuse atrophy, found in 217 eyes without choroidal neovascularization (CNV) or lacquer cracks (LCs) at baseline, progressed in 111 (51%) eyes, leading to macular diffuse atrophy (n = 64; 64/111 or 58%), patchy atrophy (n = 59; 53%), myopic CNV (n = 18; 16%), LCs (n = 9; 5%), and patchy-related macular atrophy (n = 3; 3%). Patchy atrophy, detected in 63 eyes without CNV or LCs at baseline, showed progression in 60 eyes (95%), leading to enlargement of original patchy atrophy (n = 59; 59/60 or 98%), new patchy atrophy (n = 29; 48%), CNV-related macular atrophy (n = 13; 22%), and patchy-related macular atrophy (n = 5; 8%). Of 66 eyes with LCs, 43 eyes (65%) showed progression with development of new patchy atrophy (n = 38; 38/43 or 88%) and new LCs (n = 7; 16%). Reduction in best-corrected visual acuity (BCVA) was associated mainly (all P < 0.001) with the development of CNV or CNV-related macular atrophy and enlargement of macular atrophy. Conclusions The most frequent progression patterns were an extension of peripapillary diffuse atrophy to macular diffuse atrophy in diffuse atrophy, enlargement of the original atrophic lesion in patchy atrophy, and development of patchy atrophy in LCs. Main risk factors for progression were older age, longer axial length, and development of PPA.
The Discrepancy between Subjective and Objective Measures of Convergence Insufficiency in Whiplash-Associated Disorder versus Control Participants Ophthalmology (IF 8.204) Pub Date : 2018-01-19 Hadas Stiebel-Kalish, Amir Amitai, Michael Mimouni, Michael Bach, Tal Saban, Michelle Cahn, Liat Gantz
Purpose Motor vehicle accidents (MVAs) are a pandemic associated with human suffering and a burden to national economies. Whiplash-associated disorders (WADs) after MVAs are associated commonly with disability claims, many of which are related to vision. Convergence insufficiency (CI) leads to visual disability associated with symptoms of ocular discomfort. We examined the incidence of symptoms and findings consistent with CI in a cohort of patients after MVA-related WAD compared with age-matched control participants. Design Prospective cohort study. Participants Patients with WAD after MVA were recruited from the Orthopedic Emergency Department between July 2014 and March 2017. Control participants were recruited among hospital personnel and relatives of WAD patients. Methods The Convergence Insufficiency Symptom Survey (CISS) questionnaire was completed by each participant, followed by a detailed visual examination including measurements of distance and near best-corrected Snellen visual acuity, distance and near cover test, Randot stereopsis, Maddox distance and Maddox-Thorington near heterophoria, near point of convergence, base-out step fusional reserves, and amplitude of accommodation using the push-away method. Main Outcome Measures The CISS score and binocular measure findings of CI were recorded and analyzed using Student's t test, the chi-square test, and multiple logistic regression adjusted for age and gender. Results A pathologic CISS score of 16 or more occurred in 26 of 57 WAD patients (45.6%) compared with 6 of 39 control participants (15.4%; P = 0.002). Absolute CISS score was higher in the WAD group compared with the control group (15.3±10.0 vs. 7.7±7.7; P < 0.001). Findings consistent with CI occurred in 7.0% of WAD patients and 7.7% of control participants (P = 0.90). Conclusions Visual symptoms suggestive of CI were reported more frequently among WAD patients compared with control participants, yet the incidence of examination findings indicating weakness of convergence was not increased. The discrepancy between subjective and objective measures of CI in WAD patients versus control participants stresses the importance of training healthcare personnel to assess disability using objective, validated standards of examination.
Vitreoretinal Complications and Outcomes in 92 Eyes Undergoing Surgery for Modified Osteo-Odonto-Keratoprosthesis : A 10-Year Review Ophthalmology (IF 8.204) Pub Date : 2018-01-17 Pukhraj Rishi, Ekta Rishi, Vishvesh Agarwal, Sridevi Nair, Geetha Iyer, Bhaskar Srinivasan, Shweta Agarwal
Purpose To analyze vitreoretinal (VR) complications and treatment outcomes in eyes undergoing modified osteo-odonto-keratoprosthesis (OOKP) surgery. Design Retrospective case series. Participants All patients who underwent modified OOKP (mOOKP) surgery at a tertiary eye-care center from March 2003 to February 2013 were included. Methods Medical records were reviewed for relevant medical history, best-corrected visual acuity (BCVA), slit-lamp examination, ultrasound scan, oral examination findings, and VR complications. Main Outcome Measures The BCVA at the last visit. Optimal anatomic outcome was attached retina with a normal intraocular pressure at the last visit. Results A total of 92 eyes of 90 patients were included. Indications for OOKP included Stevens–Johnson syndrome (n = 53), chemical injury (n = 36), and ocular cicatricial pemphigoid (n = 3). A total of 41 eyes of 39 patients developed VR complications, including vitritis (n = 21), retinal detachment (RD) (n = 12; primary RD = 5), retroprosthetic membrane (RPM) (n = 10; primary RPM = 2), endophthalmitis (n = 8), vitreous hemorrhage (VH) (n = 5; primary VH = 1), serous choroidal detachment (n = 5), hemorrhagic choroidal detachment (n = 2), and leak-related hypotony (n = 1). Mean interval from mOOKP surgery to occurrence of VR complication(s) was 43.8 months (median, 41.9 months; range, 0.2–95.5 months). After treatment of VR complication, visual improvement was seen in 17 eyes (42%) (mean improvement = 1.2 logarithm of the minimum angle of resolution [logMAR]; median, 0.8 logMAR; range, 0.1–2.5 logMAR), visual decline in 7 eyes (14%) (mean decline in BCVA = 0.6 logMAR; median, 0.4 logMAR; range, 0.3–1.8 logMAR), and no change in BCVA in 17 eyes (42%). However, BCVA ≥6/60 was retained in 19 eyes and ≥6/18 was retained in 9 eyes after final VR treatment. Conclusions Vitreoretinal complications constitute a significant cause of visual morbidity in eyes undergoing mOOKP surgery and pose a challenging situation to manage. However, appropriate and timely intervention can achieve encouraging results.
The 2016 American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) Database : Characteristics and Methods Ophthalmology (IF 8.204) Pub Date : 2018-01-17 Michael F. Chiang, Alfred Sommer, William L. Rich, Flora Lum, David W. Parke II
Purpose To describe the characteristics of the patient population included in the 2016 IRIS® Registry (Intelligent Research in Sight) database for analytic aims. Design Description of a clinical data registry. Participants The 2016 IRIS Registry database consists of 17 363 018 unique patients from 7200 United States–based ophthalmologists in the United States. Methods Electronic health record (EHR) data were extracted from the participating practices and placed into a clinical database. The approach can be used across dozens of EHR systems. Main Outcome Measures Demographic characteristics. Results The 2016 IRIS Registry database includes data about patient demographics, top-coded disease conditions, and visit rates. Conclusions The IRIS Registry is a unique, large, real-world data set that is available for analytics to provide perspectives and to learn about current ophthalmic care and treatment outcomes. The IRIS Registry can be used to answer questions about practice patterns, use, disease prevalence, clinical outcomes, and the comparative effectiveness of different treatments. Limitations of the data are the same limitations associated with EHR data in terms of documentation errors or missing data and the lack of images. Currently, open access to the database is not available, but there are opportunities for researchers to submit proposals for analyses, for example through a Research to Prevent Blindness and American Academy of Ophthalmology Award for IRIS Registry Research.
Iris Melanoma Outcomes Based on the American Joint Committee on Cancer Classification (Eighth Edition) in 432 Patients Ophthalmology (IF 8.204) Pub Date : 2018-01-17 Carol L. Shields, Maura Di Nicola, Vladislav P. Bekerman, Swathi Kaliki, Carolina Alarcon, Enzo Fulco, Jerry A. Shields
Purpose The American Joint Committee on Cancer (AJCC) classification was updated to the eighth edition in January 2017, providing staging for iris melanoma. This study evaluated outcomes of iris melanoma per the AJCC classification, eighth edition. Design Retrospective case series. Participants Four hundred thirty-two patients with iris melanoma. Methods Management including tumor resection, plaque radiotherapy, or enucleation. Main Outcome Measures Local tumor recurrence, melanoma-related systemic metastasis, and melanoma-related death. Results Of 432 patients with iris melanoma, AJCC classification was category T1 (n = 324 [75%]), T2 (n = 83 [19%]), T3 (n = 2 [<1%]), and T4 (n = 23 [5%]). There was no difference in age, race, gender, eye, or iris color among T categories. Overall, Kaplan-Meier analysis of outcomes (at 5 and 10 years) revealed visual acuity reduction by 3 lines or more (42% and 54%, respectively), secondary glaucoma (29% and 33%, respectively), local recurrence (8% and 17%, respectively), secondary enucleation (12% and 19%, respectively), lymph node metastasis (1% and 1%, respectively), melanoma-related systemic metastasis (5% and 10%, respectively), and melanoma-related death (3% and 4%, respectively). Compared with T1 category, the hazard ratio (HR) for local recurrence in nonenucleated eyes was 1.31 for T2, not evaluable (NE) for T3 (because of small cohort), and 6.61 for T4; the HR for metastasis was 3.41 for T2, NE for T3 (because of small cohort), and 25.6 for T4; the HR for death was 7.51 for T2, NE for T3 (because of small cohort), and 26.5 for T4; and the odds ratio for enucleation was 1.23 for T2, 3.63 for T3, and 4.72 for T4. Features predictive of melanoma-related metastasis (multivariate analysis) included secondary glaucoma (P < 0.001; HR, 4.51), T2 category (vs. T1; P = 0.01; HR, 4.09), and T4 category (vs. T1; P < 0.001; HR, 30.8). Features predictive of melanoma-related death (multivariate analysis) included older age (P = 0.008; HR, 2.16 per 10-year increase), T2 category (vs. T1; P = 0.005; HR, 8.07), and T4 category (vs. T1; P < 0.001; HR, 20.3). Conclusions The AJCC eighth edition classification provides prognostic stratification of iris melanoma. By multivariate analysis, the ratio for melanoma-related metastasis was 4 times greater in category T2 and 31 times greater in T4 compared with T1. The ratio for melanoma-related death was 8 times greater in category T2 and 20 times greater in T4 compared with T1. The cohort size for T3 was too small to provide useful information.
Review of Ophthalmology Medical Professional Liability Claims in the United States from 2006 through 2015 Ophthalmology (IF 8.204) Pub Date : 2018-01-17 Atalie C. Thompson, P. Divya Parikh, Eleonora M. Lad
Purpose To describe characteristics of closed medical professional liability (MPL) claims against ophthalmologists in the United States. Design Retrospective analysis of MPL claims from 2006-2015. Data were obtained from the Physician Insurers Association of America (PIAA) Data Sharing Project (DSP). Comparison was made between ophthalmology and all healthcare specialties for physician demographics, prevalence and costs associated with closed claims, and resolution of claims. The most prevalent chief medical factor, presenting medical condition, operative procedure, outcomes, and resolution of ophthalmology claims were compared between the 2006-2010 and 2011-2015 periods. Participants From 2006-2015, 90 743 MPL claims were closed: 2.6% (2325/90 743) of closed claims and 2.2% (564/24 670) of all paid claims were against ophthalmologists. Methods Retrospective analysis of MPL claims captured by the PIAA DSP over a 10-year period. Main Outcome Measures Subspecialty pertaining to the claim, number of claims closed and paid, indemnity paid, allocated loss adjustment expenses, chief medical factor, presenting medical condition, operative procedure, outcome, and resolution. Results Only 24% of closed claims against ophthalmologists resulted in payment. Two-thirds were dropped, withdrawn, or dismissed. Ninety percent of claims that received a verdict were favorable toward the ophthalmologist. Cataract and cornea surgeries were the most prevalent and most costly operative procedures, accounting for 50% of all claims and $47 641 376 and $32 570 148 in total paid indemnity, respectively. Average indemnity was higher for corneal procedures ($304 476) than vitreoretinal procedures ($270 141) or oculoplastic procedures on the eyelid ($222 471) or orbit and eyeball ($183 467). The prevalence and cost of claims related to endophthalmitis declined from 2006-2010 (n = 38/1160 [3.3%]; average indemnity, $516 875) period to the 2011-2015 (n = 26/1165 [2.2%]; average indemnity, $247 083) period. Average indemnity paid ($280 227 vs. $335 578) and amount spent on legal defense ($41 450 vs. $46 391) was slightly lower among ophthalmologists compared with all healthcare specialties, respectively. Conclusions Ophthalmology has a relatively low number of malpractice claims reported compared with other healthcare specialties and shows less spending on average indemnity and defense. Further studies are needed to investigate the reasons for the higher prevalence of claims related to cataract and corneal surgeries and the higher average indemnity paid for corneal procedures relative to vitreoretinal or oculoplastic procedures.
The Real-World Effect of Intravitreous Anti–Vascular Endothelial Growth Factor Drugs on Intraocular Pressure : An Analysis Using the IRIS Registry Ophthalmology (IF 8.204) Pub Date : 2018-01-11 Elizabeth A. Atchison, Kevin M. Wood, Cynthia G. Mattox, Catherine N. Barry, Flora Lum, Mathew W. MacCumber
Purpose To identify sustained differences in intraocular pressure (IOP) after intravitreous injections of anti–vascular endothelial growth factor (VEGF) drugs. Design Database study. Participants Patients seeing an ophthalmic provider who contributes to the database. Methods We identified a total of 23 776 unique patients who received only a single type of anti-VEGF medication (bevacizumab, aflibercept, or ranibizumab) by injection in the right eye in the American Academy of Ophthalmology Intelligent Research in Sight Registry. Subgroups included patients with age-related macular degeneration only and patients who had not received an anti-VEGF injection for at least 1 year before the study. We examined those with at least 12, 18, and 25 injections for each of these 3 medications. For all groups, we used fellow, untreated eyes for comparison. Main Outcome Measures The mean change in IOP from baseline at a minimum of 1 year of follow-up and the proportion of eyes with a clinically significant IOP increase (defined as sustained rise of at least 6 mmHg to an IOP of more than 21 mmHg). Results All patients in all groups receiving all drugs showed a decrease in IOP from baseline, with a mean of 0.9 mmHg in treated eyes compared with an average decrease of 0.2 mmHg in fellow untreated eyes, a statistically significant difference. A generalized linear model accounting for confounders associated bevacizumab with slightly less lowering of IOP than aflibercept and ranibizumab in most subgroups. A clinically significant IOP increase was seen in 2.6% of eyes receiving injections compared with 1.5% in the associated untreated fellow eyes. Clinically significant IOP increases occurred at a rate of 1.9%, 2.8%, and 2.8% for aflibercept, ranibizumab, and bevacizumab, respectively, which was significantly higher than untreated fellow eyes for bevacizumab and ranibizumab, but not for aflibercept. Conclusions These analyses from real-world data indicate that anti-VEGF intravitreous injections are associated with a small but statistically significant decrease in IOP over time. A proportion of patients, on average 2.6%, experienced a sustained clinically significant IOP rise with these drugs overall compared with 1.5% in the fellow untreated eyes. However, such an increase was not seen with aflibercept.
Targeted Retinal Photocoagulation for Diabetic Macular Edema with Peripheral Retinal Nonperfusion : Three-Year Randomized DAVE Trial Ophthalmology (IF 8.204) Pub Date : 2018-01-11 David M. Brown, William C. Ou, Tien P. Wong, Rosa Y. Kim, Daniel E. Croft, Charles C. Wykoff
Purpose To evaluate the effect of targeted retinal photocoagulation (TRP) on visual and anatomic outcomes and treatment burden in eyes with diabetic macular edema (DME). Design Phase I/II prospective, randomized, controlled clinical trial. Participants Forty eyes of 29 patients with center-involved macular edema secondary to diabetes mellitus. Methods Eyes with center-involved DME and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/32 and 20/320 (Snellen equivalent) were randomized 1:1 to monotherapy with 0.3 mg ranibizumab (Lucentis, Genentech, South San Francisco, CA) or combination therapy with 0.3 mg ranibizumab and TRP guided by widefield fluorescein angiography. All eyes received 4 monthly ranibizumab injections followed by monthly examinations and pro re nata (PRN) re-treatment through 36 months. Targeted retinal photocoagulation was administered outside the macula to areas of retinal capillary nonperfusion plus a 1–disc area margin in the combination therapy arm at week 1, with re-treatment at months 6, 18, and 25, if indicated. Main Outcome Measures Mean change in ETDRS BCVA from baseline and number of intravitreal injections administered. Results At baseline, mean age was 55 years, mean BCVA was 20/63 (Snellen equivalent), and mean central retinal subfield thickness (CRT) was 530 μm. Thirty-four eyes (85%) completed month 36, at which point mean BCVA improved 13.9 and 8.2 letters (P = 0.20) and mean CRT improved 302 and 152 μm (P = 0.03) in the monotherapy and combination therapy arms, respectively. The mean number of injections administered through month 36 was 24.4 (range, 10–34) and 27.1 (range, 12–36), with 73% (362/496) and 80% (433/538) of PRN injections administered (P = 0.004) in the monotherapy and combination therapy arms, respectively. Goldmann visual field isopter III-4e area decreased by 2% and 18% in the monotherapy and combination therapy arms, respectively (P = 0.30). Conclusions In this 3-year randomized trial of 40 eyes with DME, there was no evidence that combination therapy with ranibizumab and TRP improved visual outcomes or reduced treatment burden compared with ranibizumab alone.
Polypoidal Choroidal Vasculopathy : Definition, Pathogenesis, Diagnosis, and Management Ophthalmology (IF 8.204) Pub Date : 2018-01-10 Chui Ming Gemmy Cheung, Timothy Y.Y. Lai, Paisan Ruamviboonsuk, Shih-Jen Chen, Youxin Chen, K. Bailey Freund, Fomi Gomi, Adrian H. Koh, Won-Ki Lee, Tien Yin Wong
Polypoidal choroidal vasculopathy (PCV) is an age-related macular degeneration (AMD) subtype and is seen particularly in Asians. Previous studies have suggested disparity in response to intravitreal injections of anti–vascular endothelial growth factor (VEGF) agents between PCV and typical AMD, and thus, the preferred treatment for PCV has remained unclear. Recent research has provided novel insights into the pathogenesis of PCV, and imaging studies based on OCT suggest that PCV belongs to a spectrum of conditions characterized by pachychoroid, in which disturbance in the choroidal circulation seems to be central to its pathogenesis. Advances in imaging, including enhanced depth imaging, swept-source OCT, en face OCT, and OCT angiography, have facilitated the diagnosis of PCV. Importantly, 2 large, multicenter randomized clinical trials evaluating the safety and efficacy of anti-VEGF monotherapy and combination with photodynamic therapy (PDT) recently reported initial first-year outcomes, providing level I evidence to guide clinicians in choosing the most appropriate therapy for PCV. In this review, we summarize the latest updates in the epidemiologic features, pathogenesis, and advances in imaging and treatment trials, with a focus on the most recent key clinical trials. Finally, we propose current management guidelines and recommendations to help clinicians manage patients with PCV. Remaining gaps in current understanding of PCV, such as significance of polyp closure, high recurrence rate, and heterogeneity within PCV, are highlighted where further research is needed.
Glaucomatous Optic Neuropathy Associated with Nocturnal Dip in Blood Pressure : Findings from the Maracaibo Aging Study Ophthalmology (IF 8.204) Pub Date : 2018-01-06 Jesús D. Melgarejo, Joseph H. Lee, Michele Petitto, Juan B. Yépez, Felipe A. Murati, Zhezhen Jin, Carlos A. Chávez, Rosa V. Pirela, Gustavo E. Calmón, Winston Lee, Matthew P. Johnson, Luis J. Mena, Lama A. Al-Aswad, Joseph D. Terwilliger, Rando Allikmets, Gladys E. Maestre, C. Gustavo De Moraes
Purpose To determine which nocturnal blood pressure (BP) parameters (low levels or extreme dipper status) are associated with an increased risk of glaucomatous damage in Hispanics. Design Observational cross-sectional study. Participants A subset (n = 93) of the participants from the Maracaibo Aging Study (MAS) who met the study eligibility criteria were included. These participants, who were at least 40 years of age, had measurements for optical tomography coherence, visual field (VF) tests, 24-hour BP, office BP, and intraocular pressure <22 mmHg. Methods Univariate and multivariate logistic regression analyses under the generalized estimating equations (GEE) framework were used to examine the relationships between glaucomatous damage and BP parameters, with particular attention to decreases in nocturnal BP. Main Outcome Measures Glaucomatous optic neuropathy (GON) based on the presence of optic nerve damage and VF defects. Results The mean age was 61.9 years, and 87.1% were women. Of 185 eyes evaluated, 50 (27.0%) had signs of GON. Individuals with GON had significantly lower 24-hour and nighttime diastolic BP levels than those without. However, results of the multivariate GEE models indicated that the glaucomatous damage was not related to the average systolic or diastolic BP levels measured over 24 hours, daytime, or nighttime. In contrast, extreme decreases in nighttime systolic and diastolic BP (>20% compared with daytime BP) were significant risk factors for glaucomatous damage (odds ratio, 19.78 and 5.55, respectively). Conclusions In this population, the link between nocturnal BP and GON is determined by extreme dipping effects rather than low nocturnal BP levels alone. Further studies considering extreme decreases in nocturnal BP in individuals at high risk of glaucoma are warranted.
Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy Ophthalmology (IF 8.204) Pub Date : 2018-01-06 Kamron N. Khan, Melissa Kasilian, Omar A.R. Mahroo, Preena Tanna, Angelos Kalitzeos, Anthony G. Robson, Kazushige Tsunoda, Takeshi Iwata, Anthony T. Moore, Kaoru Fujinami, Michel Michaelides
Purpose To describe the earliest features of ABCA4-associated retinopathy. Design Case series. Participants Children with a clinical and molecular diagnosis of ABCA4-associated retinopathy without evidence of macular atrophy. Methods The retinal phenotype was characterized by color fundus photography, OCT, fundus autofluorescence (FAF) imaging, electroretinography, and in 2 patients, adaptive optics scanning laser ophthalmoscopy (AOSLO). Sequencing of the ABCA4 gene was performed in all patients. Main Outcome Measures Visual acuity, OCT, FAF, electroretinography, and AOSLO results. Results Eight children with ABCA4-associated retinopathy without macular atrophy were identified. Biallelic variants in ABCA4 were identified in all patients. Four children were asymptomatic, and 4 reported loss of VA. Patients were young (median age, 8.5 years; interquartile range, 6.8 years) with good visual acuity (median, 0.155 logarithm of the minimum angle of resolution [logMAR]; interquartile range, 0.29 logMAR). At presentation, the macula appeared normal (n = 3), had a subtly altered foveal reflex (n = 4), or demonstrated manifest fine yellow dots (n = 1). Fundus autofluorescence identified hyperautofluorescent dots in the central macula in 3 patients, 2 of whom showed a normal fundus appearance. Only 1 child had widespread hyperautofluorescent retinal flecks at presentation. OCT imaging identified hyperreflectivity at the base of the outer nuclear layer in all 8 patients. Where loss of outer nuclear volume was evident, this appeared to occur preferentially at a perifoveal locus. Longitudinal split-detector AOSLO imaging in 2 individuals confirmed that the greatest change in cone spacing occurred in the perifoveal, and not foveolar, photoreceptors. Electroretinography showed a reduced B-wave–to–A-wave ratio in 3 of 5 patients tested; in 2 children, recordings clearly showed electronegative results. Conclusions In childhood-onset ABCA4-associated retinopathy, the earliest stages of macular atrophy involve the parafovea and spare the foveola. In some cases, these changes are predated by tiny, foveal, yellow, hyperautofluorescent dots. Hyperreflectivity at the base of the outer nuclear layer, previously described as thickening of the external limiting membrane, is likely to represent a structural change at the level of the foveal cone nuclei. Electroretinography suggests that the initial site of retinal dysfunction may occur after phototransduction.
Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci in Patients with Early Stages of Angle-Closure Disease Ophthalmology (IF 8.204) Pub Date : 2018-01-06 Monisha E. Nongpiur, Ching-Yu Cheng, Roopam Duvesh, Saravanan Vijayan, Mani Baskaran, Chiea-Chuen Khor, John Allen, Srinivasan Kavitha, Rengaraj Venkatesh, David Goh, Rahat Husain, Pui Yi Boey, Desmond Quek, Ching Lin Ho, Tina T. Wong, Shamira Perera, Tien Yin Wong, Subbiah R. Krishnadas, Periasamy Sundaresan, Tin Aung, Eranga N. Vithana
Purpose To investigate whether newly identified genetic loci for primary angle-closure glaucoma (PACG) are associated with early stage angle-closure disease defined as primary angle closure suspect (PACS). Design Case-control study. Participants A total of 1397 PACS patients and 943 controls of Chinese ethnicity from Singapore and 604 PACS patients and 287 controls of Indian ethnicity. Methods The 8 PACG single nucleotide polymorphisms (SNPs; rs11024102 at PLEKHA7, rs3753841 at COL11A1, rs1015213 located between PCMTD1 and ST18 son chromosome 8q, rs3816415 at EPDR1, rs1258267 at CHAT, rs736893 at GLIS3, rs7494379 at FERMT2, and rs3739821 mapping in between DPM2 and FAM102A) were genotyped by Taqman assays. The association between SNP genotypes and PACS status was measured using logistic regression. A P value of 0.006 was set to account for the testing of 8 genetic loci using a Bonferroni correction. A meta-analysis was conducted to calculate the overall P value and accompanying per-allele odds ratios for each SNP analyzed. Main Outcome Measures Association of PACG loci with PACS status. Results The PACS patients were significantly older in both cohorts (Chinese, P < 0.001; Indian, P = 0.002), and there were also more women (P < 0.001, both Chinese and Indian cohorts). In the Chinese cohort, significant evidence of association was noted at 3 SNPs: rs1015213 [A] in PCMTD1-ST18 (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.36–4.11; P = 0.002), rs3816415 [A] in EPDR1 (OR, 1.49; 95% CI, 1.19–1.85; P < 0.001), and rs3739821 [G] in DPM2-FAM102A (OR, 1.40; 95% CI, 1.18–1.65; P < 0.001). Only PCMTD1-ST-18 was replicated modestly in the Indian population (P = 0.056). Meta-analysis showed significant evidence of association for PCMTD1-ST-18 (OR, 1.55; 95% CI, 1.18–2.04; P = 0.002) and DPM2-FAM102A (OR, 1.27; 95% CI, 1.12–1.45; P = 0.0002). Conclusions In this study, 2 of 8 PACG-associated loci were associated significantly with PACS status, the earliest stage in the angle-closure glaucoma disease course. The association of these PACG loci with PACS status suggests that these loci may confer susceptibility to a narrow angle configuration.
Guidance on Noncorticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis : Fundamentals Of Care for UveitiS (FOCUS) Initiative Ophthalmology (IF 8.204) Pub Date : 2018-01-06 Andrew D. Dick, James T. Rosenbaum, Hassan A. Al-Dhibi, Rubens Belfort Jr., Antoine P. Brézin, Soon Phaik Chee, Janet L. Davis, Athimalaipet V. Ramanan, Koh-Hei Sonoda, Ester Carreño, Heloisa Nascimento, Sawsen Salah, Sherveen Salek, Jay Siak, Laura Steeples
Topic An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic review of the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE, CINAHL, SCOPUS, BIOSIS, and Web of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review. A total of 44 globally representative group members met in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents.
Nationwide Prevalence of Self-Reported Serious Sensory Impairments and Their Associations with Self-Reported Cognitive and Functional Difficulties Ophthalmology (IF 8.204) Pub Date : 2018-01-04 Spencer D. Fuller, Lucy I. Mudie, Carlos Siordia, Bonnielin K. Swenor, David S. Friedman
Purpose To estimate the nationwide prevalence of self-reported serious vision impairment (SVI), serious hearing impairment (SHI), and serious dual sensory impairment (DSI; i.e., concomitant SVI and SHI) and to characterize their associations with self-reported cognitive, independent living, self-care, and ambulatory difficulties. Design The American Community Survey (ACS) is a nationwide cross-sectional survey administered by the United States Census Bureau. Participants The 2011–2015 ACS sample contains data on 7 210 535 individuals 45 years of age or older. Methods Descriptive statistics for each of the 4 mutually exclusive sensory impairment categories no sensory impairment (NSI), SVI, SHI, and serious DSI were calculated using the weighted sample. Adjusted odds ratios using several logistic regressions were calculated using the unweighted sample to measure the magnitude of associations between sensory impairment status and the outcome difficulties. Main Outcome Measures Self-reported cognitive, independent living, self-care, and ambulatory difficulty. Results Among individuals 45 years of age or older, the estimated nationwide prevalence of self-reported SVI alone is 2.8%, that of SHI alone is 6.0%, and that of serious DSI is 1.6%. The prevalence of each sensory impairment increases with age. A greater proportion of American Indians or Alaskan Natives experience SVI (4.8%), SHI (8.5%), and serious DSI (3.7%) than any other race or ethnic group (P < 0.001). Individuals reporting serious DSI are more likely to report cognitive impairment, independent living difficulty, self-care difficulty, and difficulty ambulating than individuals with NSI across all age groups (all P < 0.001). Furthermore, serious DSI is associated with greater cognitive and functional difficulties than SVI or SHI alone, and SVI alone has a greater association with cognitive and functional difficulties than SHI alone. Conclusions The nationwide prevalence of self-reported serious sensory impairment increases with age and is distributed unequally among different racial and ethnic groups. Any sensory impairment is associated with greater cognitive and functional difficulties than NSI. Additionally, serious DSI is associated with greater difficulties than SVI or SHI alone, and SVI alone is more serious than SHI alone in each of the 4 cognitive and functional difficulties.
Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population : Genetic and Clinical Aspects Ophthalmology (IF 8.204) Pub Date : 2017-12-22 Adva Kimchi, Samer Khateb, Rong Wen, Ziqiang Guan, Alexey Obolensky, Avigail Beryozkin, Shoshi Kurtzman, Anat Blumenfeld, Eran Pras, Samuel G. Jacobson, Tamar Ben-Yosef, Hadas Newman, Dror Sharon, Eyal Banin
Purpose To analyze the genetic and clinical findings in retinitis pigmentosa (RP) patients of Ashkenazi Jewish (AJ) descent, aiming to identify genotype–phenotype correlations. Design Cohort study. Participants Retinitis pigmentosa patients from 230 families of AJ origin. Methods Sanger sequencing was performed to detect specific founder mutations known to be prevalent in the AJ population. Ophthalmologic analysis included a comprehensive clinical examination, visual acuity (VA), visual fields, electroretinography, color vision testing, and retinal imaging by OCT, pseudocolor, and autofluorescence fundus photography. Main Outcome Measures Inheritance pattern and causative mutation; retinal function as assessed by VA, visual fields, and electroretinography results; and retinal structural changes observed on clinical funduscopy as well as by pseudocolor, autofluorescence, and OCT imaging. Results The causative mutation was identified in 37% of families. The most prevalent RP-causing mutations are the Alu insertion (c.1297_8ins353, p.K433Rins31*) in the male germ cell-associated kinase (MAK) gene (39% of families with a known genetic cause for RP) and c.124A>G, p.K42E in dehydrodolichol diphosphate synthase (DHDDS) (33%). Additionally, disease-causing mutations were identified in 11 other genes. Analysis of clinical parameters of patients with mutations in the 2 most common RP-causing genes revealed that MAK patients had better VA and visual fields at relatively older ages in comparison with DHDDS patients. Funduscopic findings of DHDDS patients matched those of MAK patients who were 20 to 30 years older. Patients with DHDDS mutations were referred for electrophysiologic evaluation at earlier ages, and their cone responses became nondetectable at a much younger age than MAK patients. Conclusions Our AJ cohort of RP patients is the largest reported to date and showed a substantial difference in the genetic causes of RP compared with cohorts of other populations, mainly a high rate of autosomal recessive inheritance and a unique composition of causative genes. The most common RP-causing genes in our cohort, MAK and DHDDS, were not described as major causative genes in other populations. The clinical data show that in general, patients with biallelic MAK mutations had a later age of onset and a milder retinal phenotype compared with patients with biallelic DHDDS mutations.
The Primary Tube Versus Trabeculectomy Study : Methodology of a Multicenter Randomized Clinical Trial Comparing Tube Shunt Surgery and Trabeculectomy with Mitomycin C Ophthalmology (IF 8.204) Pub Date : 2017-12-18 Steven J. Gedde, Philip P. Chen, Dale K. Heuer, Kuldev Singh, Martha M. Wright, William J. Feuer, Joyce C. Schiffman, Wei Shi
Purpose To describe the methodology of the Primary Tube Versus Trabeculectomy (PTVT) Study. Design Multicenter randomized clinical trial. Participants Patients with medically uncontrolled glaucoma and no prior incisional ocular surgery. Methods Patients are being enrolled at 16 clinical centers and randomly assigned to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (0.4 mg/ml for 2 minutes). Main Outcome Measures The primary outcome measure is the rate of surgical failure, defined as intraocular pressure (IOP) more than 21 mmHg or reduced by less than 20% from baseline, IOP of 5 mmHg or less, reoperation for glaucoma, or loss of light perception vision. Secondary outcome measures include IOP, glaucoma medical therapy, visual acuity, visual fields, and surgical complications. Conclusions Practice patterns vary in the surgical management of glaucoma, and opinions differ among surgeons regarding the preferred primary operation for glaucoma. The PTVT Study will provide valuable information comparing the 2 most commonly performed glaucoma surgical procedures.
Fragility of Results in Ophthalmology Randomized Controlled Trials : A Systematic Review Ophthalmology (IF 8.204) Pub Date : 2017-12-11 Carl Shen, Isabel Shamsudeen, Forough Farrokhyar, Kourosh Sabri
Purpose Evidence-based medicine is guided by our interpretation of randomized controlled trials (RCTs) that address important clinical questions. Evaluation of the robustness of statistically significant outcomes adds a crucial element to the global assessment of trial findings. The purpose of this systematic review was to determine the robustness of ophthalmology RCTs through application of the Fragility Index (FI), a novel metric of the robustness of statistically significant outcomes. Design Systematic review. Methods A literature search (MEDLINE) was performed for all RCTs published in top ophthalmology journals and ophthalmology-related RCTs published in high-impact journals in the past 10 years. Two reviewers independently screened 1811 identified articles for inclusion if they (1) were a human ophthalmology-related trial, (2) had a 1:1 prospective study design, and (3) reported a statistically significant dichotomous outcome in the abstract. All relevant data, including outcome, P value, number of patients in each group, number of events in each group, number of patients lost to follow-up, and trial characteristics, were extracted. The FI of each RCT was calculated and multivariate regression applied to determine predictive factors. Results The 156 trials had a median sample size of 91.5 (range, 13–2593) patients/eyes, and a median of 28 (range, 4–2217) events. The median FI of the included trials was 2 (range, 0–48), meaning that if 2 non-events were switched to events in the treatment group, the result would lose its statistical significance. A quarter of all trials had an FI of 1 or less, and 75% of trials had an FI of 6 or less. The FI was less than the number of missing data points in 52.6% of trials. Predictive factors for FI by multivariate regression included smaller P value (P < 0.001), larger sample size (P = 0.001), larger number of events (P = 0.011), and journal impact factor (P = 0.029). Conclusions In ophthalmology trials, statistically significant dichotomous results are often fragile, meaning that a difference of only a couple of events can change the statistical significance. An application of the FI in RCTs may aid in the interpretation of results and assessment of quality of evidence.
Glaucoma after Lens-Sparing Vitrectomy for Advanced Retinopathy of Prematurity Ophthalmology (IF 8.204) Pub Date : 2017-12-11 Eric Nudleman, Ilkay Kilic Muftuoglu, Raouf Gaber, Joshua Robinson, Kimberly Drenser, Antonio Capone, Michael T. Trese
Purpose To report the incidence of, and factors related to, glaucoma after lens-sparing vitrectomy (LSV) surgery in advanced retinopathy of prematurity (ROP). Design Retrospective case series at a single tertiary referral pediatric vitreoretinal practice. Participants Four hundred and one eyes from 270 patients were included. Methods The medical records of patients who underwent LSV for stage 4A, 4B, and 5 ROP were retrospectively reviewed. Data were collected from patient charts including gender, gestational age at birth, birthweight, stage of ROP at presentation, prior treatment (laser or cryotherapy), subsequent retinal surgeries, presence of glaucoma, time to glaucoma (interval between LSV and the onset of glaucoma), date of lensectomy (if performed), and retinal attachment status at last visit. Lensectomy was considered as a time-dependent covariate in the analysis. Main Outcome Measures Incidence of glaucoma and potential risk factors for time to glaucoma. Results Among 401 eyes with advanced ROP, 40 eyes (10.0%) had glaucoma during a mean of 3.06±4.11 years of follow-up. The incidence of glaucoma was 6.9% (17/247) in stage 4A, 12.0% (16/133) in stage 4B, and 33.3% (7/21) in stage 5 ROP. Twenty-one percent of eyes (87/401) required lensectomy at a mean of 1.23±2.19 years after LSV. In univariate analysis, having stage 5 ROP (vs. stage 4 ROP) and presence of lensectomy were found to be significantly associated with time to glaucoma (hazard ratio = 6.76, 95% confidence interval = 2.19–20.88, P = 0.001; hazard ratio = 3.06, 95% confidence interval = 1.56–6.0, P = 0.001, respectively). In multivariate analysis, lensectomy was the only significant independent factor associated with time to glaucoma (hazard ratio = 2.76, 95% confidence interval = 1.371–5.581, P = 0.004). Conclusions Patients with more severe ROP had a higher incidence of glaucoma after lens-sparing vitrectomy. If a patient required lensectomy owing to progression of ROP and/or presence of lens opacity, then the hazard of having glaucoma significantly increased compared with those without lensectomy.
Association of Rare Predicted Loss-of-Function Variants in Cellular Pathways with Sub-Phenotypes in Age-Related Macular Degeneration Ophthalmology (IF 8.204) Pub Date : 2017-12-08 Alexandra Pietraszkiewicz, Freekje van Asten, Alan Kwong, Rinki Ratnapriya, Goncalo Abecasis, Anand Swaroop, Emily Y. Chew
Purpose To investigate the association of rare predicted loss-of-function (pLoF) variants within age-related macular degeneration (AMD) risk loci and AMD sub-phenotypes. Design Case-control study. Participants Participants of AREDS, AREDS2, and Michigan Genomics Initiative. Methods Whole genome sequencing data were analyzed for rare pLoF variants (frequency <0.1%) in the regions of previously identified 52 independent risk variants known to be associated with AMD. Frequency of the rare pLoF variants in cases with intermediate or advanced AMD was compared with controls. Variants were assigned to the complement, extracellular matrix (ECM), lipid, cell survival, immune system, metabolism, or unknown/other pathway. Associations of rare pLoF variant pathways with AMD sub-phenotypes were analyzed using logistic and linear regression, and Cox proportional hazards models. Main Outcome Measures Differences in rare pLoF variant pathway burden and association of rare pLoF variant pathways with sub-phenotypes within the population with AMD were evaluated. Results Rare pLoF variants were found in 298 of 1689 cases (17.6%) and 237 of 1518 controls (15.6%) (odds ratio [OR], 1.11; 95% confidence interval [CI], 0.91–1.36; P = 0.310). An enrichment of rare pLoF variants in the complement pathway in cases versus controls (OR, 2.94; 95% CI, 1.49–5.79; P = 0.002) was observed. Within cases, associations between all rare pLoF variants and choroidal neovascularization (CNV) (OR, 1.34; 95% CI, 1.04–1.73; P = 0.023), calcified drusen (OR, 1.33; 95% CI, 1.04–1.72; P = 0.025), higher scores on the AREDS Extended AMD Severity Scale (Standardized Coefficient Beta (β)=0.346 [0.086–0.605], P = 0.009), and progression to advanced disease (hazard ratio, 1.25; 95% CI, 1.01–1.55; P = 0.042) were observed. At the pathway level, there were associations between the complement pathway and geographic atrophy (GA) (OR, 2.17; 95% CI, 1.12–4.24; P = 0.023), the complement pathway and calcified drusen (OR, 3.75; 95% CI, 1.79–7.86; P < 0.001), and the ECM pathway and more severe levels in the AREDS Extended AMD Severity Scale (β = 0.62; 95% CI, 0.04–1.20; P = 0.035). Conclusions Rare pLoF variants are associated with disease progression. Variants in the complement pathway modify the clinical course of AMD and increase the risk of developing specific sub-phenotypes.
Central Visual Field Damage and Parapapillary Choroidal Microvasculature Dropout in Primary Open-Angle Glaucoma Ophthalmology (IF 8.204) Pub Date : 2017-12-08 Eun Ji Lee, Tae-Woo Kim, Ji-Ah Kim, Jeong-Ah Kim
Purpose To determine whether microvasculature dropout (MvD) in the parapapillary choroid is related to the presence of central visual field defects in primary open-angle glaucoma (POAG). Design Cross-sectional observational study. Participants Thirty-two POAG patients with an initial parafoveal scotoma (IPFS) within a 10° radius in 1 hemifield and 42 POAG patients with an initial nasal step (INS) within the nasal periphery outside 10° of fixation in 1 hemifield. Methods The peripapillary choroidal microvasculature was evaluated on en face images obtained using swept-source OCT angiography. Microvasculature dropout was defined as a focal sectoral capillary dropout with no visible microvascular network identified in the choroidal layer. Factors associated with IPFS, compared with INS, were assessed using logistic regression analyses. Main Outcome Measures Factors associated with IPFS rather than INS. Results Microvasculature dropout was observed in 25 of 32 eyes (78.1%) in the IPFS group, but in only 1 of 42 eyes (2.4%) in the INS group (P < 0.001). In logistic regression analyses, only MvD was a significant factor influencing the presence of IPFS. Systemic risk factors such as cold extremities (P = 0.026), migraine (P = 0.044), lower mean arterial pressure (P = 0.037), and lower ocular perfusion pressure (P = 0.024) were associated significantly with the presence of MvD. Conclusions The presence of MvD in the parapapillary choroid was a strong predictor for IPFS.
Fully Automated Detection and Quantification of Macular Fluid in OCT Using Deep Learning Ophthalmology (IF 8.204) Pub Date : 2017-12-08 Thomas Schlegl, Sebastian M. Waldstein, Hrvoje Bogunovic, Franz Endstraßer, Amir Sadeghipour, Ana-Maria Philip, Dominika Podkowinski, Bianca S. Gerendas, Georg Langs, Ursula Schmidt-Erfurth
Intracameral Chemotherapy for Globe Salvage in Retinoblastoma with Secondary Anterior Chamber Invasion Ophthalmology (IF 8.204) Pub Date : 2017-12-06 Francis L. Munier, Alexandre Moulin, Marie-Claire Gaillard, Massimo Bongiovanni, Sarah Decembrini, Susan Houghton, Maja Beck-Popovic, Christina Stathopoulos
A Study of the Natural History of Vitreomacular Traction Syndrome by OCT Ophthalmology (IF 8.204) Pub Date : 2017-12-06 Marie-Hélène Errera, Sidath E. Liyanage, Petros Petrou, Pearse A. Keane, Rene Moya, Eric Ezra, David G. Charteris, Louisa Wickham
Purpose To examine the natural history of vitreomacular traction syndrome (VMTS) in the absence of other ocular comorbidities. Design Retrospective clinical case series. Participants A total of 183 eyes of 159 patients diagnosed with VMTS with no other ocular comorbidity. Methods Patients with VMTS were identified from an OCT database at Moorfields Eye Hospital, London. Sequential OCT scans and patient notes were reviewed over a minimum period of 6 months. Data collected included patient demographics, best-corrected visual acuity, and OCT features of vitreomacular adhesion. Contingency tests and binary logistic modeling were used to identify baseline predictors of stability and progression. Main Outcome Measures The rates of spontaneous resolution (defined by release of traction), progression to full-thickness macular hole, and surgical intervention were analyzed. Results Presenting visual acuity was 0.3±0.3 logMAR units. The mean length of follow-up was 17.4±12.1 months. During this period, VMTS persisted in 60% and resolved in 20% (occurring on average at 15 months). Of the remainder, 12% developed a macular hole and 8% elected to proceed with surgery for symptoms. Focal adhesion <1500 μm was present in 87%. A premacular membrane with macular pucker (PMM) was present in 20%. With persistent VMTS, vision and central foveal thickness remained unchanged. The relative risk of resolution increased in those cases with better presenting visual acuities, lesser foveal thicknesses, and no associated PMMs; vision significantly improved in those cases with resolution. Conclusions VMTS persists in the majority of patients but despite this, visual acuities did not deteriorate significantly over the study period unless patients developed a full-thickness macular hole or required surgical intervention for symptoms. Resolution spontaneously occurred in 20%, with an improvement in vision.
Mucous Membrane Pemphigoid with Ocular Involvement: The Clinical Phenotype and Its Relationship to Direct Immunofluorescence Findings Ophthalmology (IF 8.204) Pub Date : 2017-12-06 Hon Shing Ong, Jane F. Setterfield, Darwin C. Minassian, John K. Dart
Purpose This study explored the validity of the First International Consensus on Mucous Membrane Pemphigoid (MMP) guidance, which recommends that clinically indistinguishable patients, who have direct immunofluorescence (DIF)-negative biopsies, be excluded from a diagnosis of MMP. Misdiagnosis, or delayed diagnosis, of MMP with ocular involvement leads to the inappropriate use of topical therapy, the standard of care for causes of cicatrising conjunctivitis other than MMP, rather than systemic immunomodulatory therapy, resulting in irreversible clinical deterioration in patients with MMP. Design Prospective, cross-sectional study. Participants Patients meeting the clinical criteria of ocular MMP, including those with positive and negative DIF findings. Methods A case report form was used to collect the demographic details, the clinical history, and the results of a detailed clinical assessment by ophthalmologists, otolaryngologists, dermatologists, and oral medicine specialists. All anatomic sites potentially affected by MMP were examined apart from the esophagus (and larynx in a subset). The DIF results were recorded. Main Outcome Measures Differences between DIF-positive and -negative patients in demography, sites of involvement, and disease severity as determined by the degree of conjunctival scarring (using Tauber staging), central corneal disease (vascularization, scarring, ulceration, and conjunctivalization), history of conjunctival or lid surgery, and requirement for systemic immunotherapy at the time of screening. Results A total of 73 patients with ocular MMP were recruited, of whom 20 of 73 (27.4%) had ocular-only disease. There was no significant demographic or clinical difference between patients with positive and negative DIF results. This finding included differences in disease severity for which the only significant difference was that of more severe central corneal disease in DIF-negative patients. Asymptomatic disease at different sites was frequent. Conclusions These findings do not support the classification of DIF-negative patients, meeting the clinical criteria for ocular MMP, as having a different disease. This category of patients should be accepted as having DIF-negative MMP, for clinical management purposes, with patients having inflamed eyes being treated with systemic immunomodulatory therapy. The frequent finding of asymptomatic ocular, oral, and nasopharyngeal MMP is clinically significant and implies that these sites should be routinely screened in asymptomatic patients.
Ethnic Differences in the Prevalence and Risk Factors of Diabetic Retinopathy : The Singapore Epidemiology of Eye Diseases Study Ophthalmology (IF 8.204) Pub Date : 2017-12-06 Gavin S. Tan, Alfred Gan, Charumathi Sabanayagam, Yih Chung Tham, Kumari Neelam, Paul Mitchell, Jie Jin Wang, Ecosse L. Lamoureux, Ching-Yu Cheng, Tien Y. Wong
Purpose To evaluate the prevalence and risk factors for diabetic retinopathy (DR) in the Singapore Epidemiology of Eye Diseases (SEED) Study. Design Population-based, cross-sectional study. Participants Persons of Malay, Indian, and Chinese ethnicity aged 40+ years, living in Singapore. Methods Diabetes was defined as nonfasting plasma glucose ≥200 mg/dl (11.1 mmol/l), glycated hemoglobin A1c (HbA1c) >6.5%, self-reported physician-diagnosed diabetes, or the use of glucose-lowering medication. Retinal photographs, were graded for the presence and severity of DR using the modified Airlie House classification system. Main Outcome Measures Diabetic retinopathy, diabetic macular edema (DME), vision-threatening diabetic retinopathy (VTDR), defined as the presence of severe nonproliferative or proliferative DR, or clinically significant macular edema (CSME). Results Of the 10 033 subjects, 2877 (28.7%) had diabetes and gradable photographs for analysis. The overall age-standardized prevalence (95% confidence interval [CI]) was 28.2% (25.9–30.6) for any DR, 7.6% (6.5–9.0) for DME, and 7.7% (6.6–9.0) for VTDR. Indians had a higher prevalence of any DR (30.7% vs. 26.2% in Chinese and 25.5% in Malays, P = 0.012); a similar trend was noted for any DME (P = 0.001) and CSME (P = 0.032). Independent risk factors for any DR were Indian ethnicity (odds ratio [OR], 1.41; 95% CI, 1.09–1.83, vs. Chinese), diabetes duration (OR, 1.10; 95% CI, 1.08–1.11, per year), HbA1c (OR, 1.25; 95% CI, 1.18–1.32, per %), serum glucose (OR, 1.03; 95% CI, 1.00–1.06, per mmol/l), and systolic blood pressure (OR, 1.14; 95% CI, 1.09–1.19, per 10 mmHg). Diastolic blood pressure (OR, 0.74; 95% CI, 0.65–0.84, per 10 mmHg increase), total cholesterol (OR, 0.87; 95% CI, 0.80–0.95, per mmol/l increase), and low-density lipoprotein (LDL) cholesterol (OR, 0.83; 95% CI, 0.74–0.92, per mmol/l increase) were associated with lower odds of any DR. Risk factors were largely similar across the 3 ethnic groups. Conclusions Indian Singaporeans have a higher prevalence of DR and DME compared with Chinese and Malays. Major risk factors for DR in this study were similar across the 3 ethnic groups. Addressing these risk factors may reduce the impact of DR in Asia, regardless of ethnicity.
Prospective Randomized Trial of Corneal Cross-linking Riboflavin Dosing Frequencies for Treatment of Keratoconus and Corneal Ectasia Ophthalmology (IF 8.204) Pub Date : 2017-12-02 Marianne O. Price, Kelly Fairchild, Matthew T. Feng, Francis W. Price Jr.
Purpose To investigate whether the riboflavin dosing frequency affects corneal cross-linking efficacy or safety, given that isotonic riboflavin solution is viscous and each installation coats the corneal surface with a film that absorbs some of the incident ultraviolet A light. Design Prospective, randomized, single-center equivalence trial. Participants Patients with progressive keratoconus or ectasia after refractive surgery (n = 510). Methods One eye per patient was prospectively randomized to 2-minute or 5-minute riboflavin dosing intervals with standard corneal cross-linking (epithelial removal and 30-minute irradiation with 3 mW/cm2 ultraviolet A light). Block randomization resulted in comparable representation of keratoconus and ectasia after refractive surgery in the 2 treatment arms. Treatment equivalence was assessed using the 2 one-sided test. Fellow eyes (n = 207) were treated with 5-minute dosing and considered in the safety analysis. Main Outcome Measures The primary hypothesis was equivalent change in the topography-derived maximum keratometry value from baseline to 6 months with 2-minute vs. 5-minute dosing. A ±0.75-diopter margin of equivalence for the treatment difference between dosing regimens was considered clinically relevant. Adverse events and changes from baseline to 6 months in corrected distance visual acuity (CDVA), uncorrected distance visual acuity, and minimum corneal thickness were assessed. Results The mean reduction in maximum keratometry from baseline was equivalent with 2-minute and 5-minute riboflavin dosing intervals at 6 months (0.97 and 0.76 diopters, respectively; 90% confidence interval for treatment difference, −0.23 to 0.66; per-protocol population). With both dosing intervals, the mean improvement in CDVA was 0.07 logarithm of the minimum angle of resolution or 3.5 letters at 6 months. Of the 635 study and fellow eyes examined at 6 months, 134 (21%) gained and 32 (5%) lost 2 or more lines of CDVA. Three eyes (0.4%) developed sterile infiltrates, 1 (0.1%) had delayed epithelial healing with dendrites, and 3 (0.4%) had recurrent epithelial defects. Three eyes (0.4%) were re-treated. Conclusions The 2 riboflavin dosing regimens produced equivalent reduction in the maximum keratometry value, with a favorable safety profile.
Personalized Prediction of Glaucoma Progression Under Different Target Intraocular Pressure Levels Using Filtered Forecasting Methods Ophthalmology (IF 8.204) Pub Date : 2017-12-02 Pooyan Kazemian, Mariel S. Lavieri, Mark P. Van Oyen, Chris Andrews, Joshua D. Stein
Purpose To generate personalized forecasts of how patients with open-angle glaucoma (OAG) experience disease progression at different intraocular pressure (IOP) levels to aid clinicians with setting personalized target IOPs. Design Secondary analyses using longitudinal data from 2 randomized controlled trials. Participants Participants with moderate or advanced OAG from the Collaborative Initial Glaucoma Treatment Study (CIGTS) or the Advanced Glaucoma Intervention Study (AGIS). Methods By using perimetric and tonometric data from trial participants, we developed and validated Kalman Filter (KF) models for fast-, slow-, and nonprogressing patients with OAG. The KF can generate personalized and dynamically updated forecasts of OAG progression under different target IOP levels. For each participant, we determined how mean deviation (MD) would change if the patient maintains his/her IOP at 1 of 7 levels (6, 9, 12, 15, 18, 21, or 24 mmHg) over the next 5 years. We also model and predict changes to MD over the same time horizon if IOP is increased or decreased by 3, 6, and 9 mmHg from the level attained in the trials. Main Outcome Measures Personalized estimates of the change in MD under different target IOP levels. Results A total of 571 participants (mean age, 64.2 years; standard deviation, 10.9) were followed for a mean of 6.5 years (standard deviation, 2.8). Our models predicted that, on average, fast progressors would lose 2.1, 6.7, and 11.2 decibels (dB) MD under target IOPs of 6, 15, and 24 mmHg, respectively, over 5 years. In contrast, on average, slow progressors would lose 0.8, 2.1, and 4.1 dB MD under the same target IOPs and time frame. When using our tool to quantify the OAG progression dynamics for all 571 patients, we found no statistically significant differences over 5 years between progression for black versus white, male versus female, and CIGTS versus AGIS participants under different target IOPs (P > 0.05 for all). Conclusions To our knowledge, this is the first clinical decision-making tool that generates personalized forecasts of the trajectory of OAG progression at different target IOP levels. This approach can help clinicians determine appropriate, personalized target IOPs for patients with OAG.
Peripapillary and Macular Vessel Density in Patients with Primary Open-Angle Glaucoma and Unilateral Visual Field Loss Ophthalmology (IF 8.204) Pub Date : 2017-11-22 Adeleh Yarmohammadi, Linda M. Zangwill, Patricia Isabel C. Manalastas, Nathanael J. Fuller, Alberto Diniz-Filho, Luke J. Saunders, Min Hee Suh, Kyle Hasenstab, Robert N. Weinreb
Purpose To characterize OCT angiography (OCT-A) vessel density of patients with primary open-angle glaucoma (POAG) with unilateral visual field (VF) loss. Design Cross-sectional study. Participants A total of 33 patients with POAG with a VF defect in 1 eye (mean VF mean deviation [MD], −3.9±3.1 decibels [dB]) and normal VF in the other eye (mean VF MD, −0.2±0.9 dB) and 33 healthy eyes. Methods All subjects underwent OCT-A imaging, spectral-domain (SD)-OCT imaging, and VF testing. OCT-A retinal vascular measurements were summarized as whole image vessel density (wiVD), circumpapillary vessel density (cpVD), and parafoveal vessel density (pfVD). Inter-eye differences in vascular measures, as well as SD OCT retinal nerve fiber layer (RNFL), macular ganglion cell complex (mGCC) thickness, and rim area measurements in glaucoma and healthy eyes were compared. Areas under the receiver operating characteristic curves (AUROCs) were used to evaluate diagnostic accuracy for differentiating between unaffected eyes of patients with POAG and healthy eyes. Main Outcome Measures Difference in OCT-A vessel density and SD OCT structural parameters between unaffected eyes of patients with POAG with the fellow affected eyes and healthy controls. Results Mean wiVD in unaffected eyes of patients with POAG (52.0%) was higher than in their fellow affected eyes (48.8%) but lower than in healthy eyes (55.9%; P < 0.001). Mean circumpapillary RNFL (cpRNFL) thickness, mGCC thickness, and rim area measurement in unaffected eyes of patients with POAG (87.5 μm, 87.7 μm, and 1.0 mm2) were also higher than those measurements in their fellow eyes (76.5 μm, 79.5 μm, and 0.8 mm2; P < 0.001) and lower than in healthy eyes (98.0 μm, 94.5 μm, and 1.4 mm2; P < 0.001). The AUROCs for differentiating unaffected eyes of patients with POAG from healthy eyes were highest for wiVD (0.84), followed by mGCC (0.78), cpRNFL (0.77), and pfVD (0.69). Conclusions OCT-A measures detect changes in retinal microvasculature before VF damage is detectable in patients with POAG, and these changes may reflect damage to tissues relevant to the pathophysiology of glaucoma. Longitudinal studies are needed to determine whether OCT-A measures can improve the detection or prediction of the onset and progression of glaucoma.
Association of Mortality with Ocular Diseases and Visual Impairment in the Age-Related Eye Disease Study 2 Ophthalmology (IF 8.204) Pub Date : 2017-11-16 , Chandana Papudesu, Traci E. Clemons, Elvira Agrón, Emily Y. Chew
Purpose To evaluate the association of mortality with visual acuity (VA) impairment, age-related macular degeneration (AMD), and cataract surgery. Design Cohort study. Participants Participants with at least intermediate AMD enrolled in a randomized controlled clinical trial of lutein/zeaxanthin and/or omega-3 fatty acids, the Age-Related Eye Disease Study 2 (AREDS2), for treatment of AMD and cataract. Methods Baseline and annual eye examinations included best-corrected visual acuity (BCVA) assessments, slit-lamp examinations, and stereoscopic fundus photographs that were centrally graded for development of late AMD (central geographic atrophy or neovascular AMD) or pseudophakia. Cause-specific mortality was determined on the basis of the International Classification of Diseases 9th or 10th Revision codes. Risk of all-cause and cause-specific mortality was assessed with Cox proportional hazards models adjusted for age, sex, AMD severity, VA, history of cataract surgery, and assigned AREDS2 study treatment. Analyses included baseline covariates: race, education, smoking status, diabetes, and cardiovascular disease. Results During follow-up (median 5 years), 368 (9%) of the 4203 AREDS2 participants died. Participants with neovascular AMD in 1 eye at baseline had a statistically significant increased risk for mortality compared with participants with no or few drusen (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.21–2.01; P < 0.001). Poorer survival was associated with bilateral cataract surgery before enrollment compared with baseline bilateral phakia (HR, 1.63; 95% CI, 1.29–2.07; P < 0.001) and with BCVA of less than 20/40 compared with participants with 20/40 or better (HR, 1.56; 95% CI, 1.06–2.30; P = 0.024), adjusted for age, sex, and statistically significant covariates. Participants who received antivascular endothelial growth factor therapies for neovascular AMD had decreased mortality compared with those who did not (HR, 0.71; 95% CI, 0.57–0.88; P = 0.002). The association between all-cause mortality and AREDS2 treatment whether assessing the main or individual treatment effect was not significantly different (omega-3 fatty acids main effect HR, 1.18; 95% CI, 0.96–1.45; P = 0.12; lutein/zeaxanthin main effect HR, 1.04; 95% CI, 0.85–1.28; P = 0.71). Conclusions In AREDS2, the presence of late AMD, bilateral cataract surgery, and VA less than 20/40 was associated with decreased survival. However, oral supplementation with omega-3 fatty acids, lutein plus zeaxanthin, zinc, or beta-carotene had no statistically significant impact on mortality.
Long-Term Visual Outcomes and Safety Profile of 27-Gauge Pars Plana Vitrectomy for Posterior Segment Disease Ophthalmology (IF 8.204) Pub Date : 2017-11-13 M. Ali Khan, Alexander Kuley, Christopher D. Riemann, Maria H. Berrocal, Rohit R. Lakhanpal, Jason Hsu, Arunan Sivalingam, Allen C. Ho, Carl D. Regillo
Purpose To report longer-term outcomes of 27-gauge pars plana vitrectomy (PPV) in eyes with posterior segment disease. Design Multicenter, retrospective, interventional case series. Participants A total of 390 eyes of 360 patients undergoing 27-gauge PPV for a vitreoretinal surgery indication. Intervention Three-port, transconjunctival, 27-gauge PPV. Main Outcome Measures Change in visual acuity (VA) and occurrence of intraoperative and postoperative complications with a minimum follow-up of 365 days. Results Mean follow-up was 715±332 days (median, 514; range, 365–1440 days). Surgical indications included epiretinal membrane (ERM) (n = 121), vitreous floaters (n = 69), diabetic tractional retinal detachment (n = 49), vitreous hemorrhage (n = 40), full-thickness macular hole (n = 33), recurrent proliferative vitreoretinopathy (PVR)–related retinal detachment (n = 18), primary rhegmatogenous retinal detachment (RRD) (n = 17), silicone oil removal (n = 16), dislocated intraocular lens (n = 10), submacular hemorrhage (n = 7), endophthalmitis (n = 6), and retained lens material (n = 4). Mean logarithm of the minimum angle of resolution (logMAR) VA improved from 0.72±0.62 (20/105 Snellen equivalent) preoperatively to 0.40±0.55 (20/50 Snellen equivalent) postoperatively (P < 0.001). No case required conversion to 23- or 25-gauge instrumentation. Postoperative complications included transient ocular hypertension in 44 eyes (11.3%), vitreous hemorrhage in 31 eyes (7.9%), and transient hypotony in 22 eyes (5.6%). Acute postoperative endophthalmitis occurred in 1 case (0.26%). Overall, 82 of 390 eyes (21.0%) underwent at least 1 additional intraocular surgery in the follow-up period, most commonly for cataract extraction (n = 40/82 eyes, 48.8%). Of the 18 eyes undergoing surgery for primary RRD, recurrent detachment due to PVR occurred in 2 eyes (11.1%). Conclusions At a minimum follow-up of 1 year, 27-gauge PPV was well tolerated with low rates of postoperative complications across varied surgical indications, including primary and complex retinal detachment.
Real-World Vision in Age-Related Macular Degeneration Patients Treated with Single Anti–VEGF Drug Type for 1 Year in the IRIS Registry Ophthalmology (IF 8.204) Pub Date : 2017-11-13 Prethy Rao, Flora Lum, Kevin Wood, Craig Salman, Bhavya Burugapalli, Rebecca Hall, Sukhminder Singh, David W. Parke, George A. Williams
Purpose The purpose of this study is to compare real-world visual acuity (VA) in patients with neovascular age-related macular degeneration (nAMD) treated with a single anti–vascular endothelial growth factor (VEGF) drug monotherapy for 1 year from the American Academy of Ophthalmology (AAO) Intelligent Research in Sight (IRIS) Registry. Design Retrospective, nonrandomized, comparative study. Participants IRIS Registry patients with nAMD who received bevacizumab, ranibizumab, or aflibercept only for 1 year between 2013–2016. Methods Participants were divided into 3 groups based on monotherapy type. Multivariate analysis of covariance models (ANCOVA) was constructed in a stepwise fashion. Main Outcome Measures The logarithm of the minimum angle of resolution (logMAR) VA at 1 year and mean change in logMAR VA between baseline and 1 year were compared between drug types. Results Of 13 859 patients, 6723 received bevacizumab, 2749 received ranibizumab, and 4387 received aflibercept only for 1 year. A total of 84 828 injections were performed. The mean number of injections (standard deviation) at 1 year was higher in the ranibizumab (6.4 [±2.4]) and aflibercept groups (6.2 [±2.4]) compared to bevacizumab group (5.9 [±2.4]; P < 0.0001). In the age-adjusted model, both ranibizumab and aflibercept achieved better logMAR VA at 1 year compared with bevacizumab (0.50 [±0.49], 0.49 [±0.44], 0.55 [±0.57]; P < 0.0001). However, this difference was not significant after multivariate adjustment (age, baseline VA, diabetes, posterior vitreous detachment, number of injections, race, insurance). There was no statistical difference in the age-adjusted or multivariate-adjusted mean logMAR VA change (standard deviation) at 1 year among treatment groups (−0.048 [0.44] bevacizumab, −0.053 [0.46] ranibizumab, −0.040 [0.39] aflibercept; P = 0.46). A higher percentage of patients achieved a ≥3-line VA improvement at 1 year in the bevacizumab group (22.7%) compared with ranibizumab (20.1%; P = 0.0093) and aflibercept (17.8%; P < 0.0001). However, after multivariate adjustment, aflibercept exhibited a greater log odds of a ≥3-line VA loss compared with bevacizumab only (1.25 log odds ratio; P < 0.0016). Conclusions This study suggests that all 3 drugs improve VA similarly over 1 year of monotherapy.
Proton Beam Therapy for Iris Melanomas in 107 Patients Ophthalmology (IF 8.204) Pub Date : 2017-11-08 Juliette Thariat, Ahmed Rahmi, Julia Salleron, Carlo Mosci, Benjamin Butet, Celia Maschi, Francesco Lanza, Sara Lanteri, Stephanie Baillif, Joel Herault, Thibaud Mathis, Jean Pierre Caujolle
Purpose To report on the clinical characteristics and outcomes for patients with iris melanoma using proton therapy. Design Retrospective study. Participants One hundred seven patients with iris melanoma from 3 regional ophthalmologic centers. Methods A retrospective study was conducted for iris melanoma patients from 3 regional ophthalmologic centers referred to and treated at a single proton therapy facility between 1996 and 2015. Main Outcome Measures At each follow-up visit, examinations included measurement of best-corrected VA, slit-lamp, examination, indirect ophthalmoscopy, and ultrasound biomicroscopy. Results With a median follow-up of 49.5 months, 5 of 107 patients experienced a local relapse within a median of 36.3 months. The cumulative incidence of relapse was 7.5% at 5 years. All 5 patients showed involvement of the iridocorneal angle (P = 0.056). Diffuse iris melanoma showed a higher risk of relapse (P = 0.044). Four patients showed out-of-field relapse and 1 showed angular relapse. Three patients were retreated with proton therapy, whereas 2 other patients, one with T1b disease and another with diffuse T3 disease, underwent secondary enucleation. None of the patients experienced metastases nor died of iris melanoma. Vision improved in 59.4% of patients (n = 60/101). However, cataracts occurred in 57.4% of the 54 patients (n = 31) without cataract or implant at diagnosis. Secondary glaucoma was reported in 7.6% of the patients (n = 8), uveitis in 4.7% (n = 5), and hyphema in 3.7% (n = 4). All but 5 cases of complications were mild, transient, and not sight limiting after treatment. Five cases of glaucoma, including 1 with uveitis, were severe and associated with visual deterioration. Conclusions Proton therapy showed efficacy and limited morbidity in iris melanomas.
Radiologic and Histopathologic Correlation of Different Growth Patterns of Metastatic Uveal Melanoma to the Liver Ophthalmology (IF 8.204) Pub Date : 2017-11-06 Albert Liao, Pardeep Mittal, David H. Lawson, Jenny J. Yang, Eszter Szalai, Hans E. Grossniklaus
Purpose The purpose of this study was to correlate magnetic resonance imaging (MRI) radiographic results with histopathologic growth patterns of metastatic uveal melanoma (UM) to the liver. Design Clinicopathologic correlation. Participants Patients with metastatic UM to the liver. Methods A retrospective review of MRI images of patients with metastatic UM to the liver at a single institution between 2004 and 2016 was performed. The MRI growth patterns were classified as nodular or diffuse. The histopathologic findings of core liver biopsies of liver metastases identified by needle localization in a subset of these patients were reviewed. The core samples were evaluated by routine light microscopy, including immunohistochemical/immunofluorescent staining for CD31, CD105, and HMB45, and classified as exhibiting an infiltrative or nodular growth pattern. Main Outcome Measures Magnetic resonance images and core biopsy findings. Results A total of 32 patients were identified with metastatic UM to the liver that was imaged by MRI, and 127 lesions were identified. A total of 46 lesions were classified by MRI as infiltrative and 81 as nodular. There were 9 needle-localized core biopsies that corresponded to MRI of metastatic lesions. Of these 9 lesions, 3 that were classified as infiltrative on MRI exhibited stage I infiltrative histologic growth patterns; of the remaining 6 that were classified as nodular by MRI, 5 histologically demonstrated stage II or stage III infiltrative growth patterns and 1 histologically demonstrated a nodular growth pattern. Conclusions Magnetic resonance imaging of hepatic infiltrative growth patterns of metastatic UM corresponded to stage I histologic infiltrative growth in the sinusoidal spaces, whereas MRI nodular growth patterns corresponded to stage II/III histologic infiltrative growth that replaced the hepatic lobule or histologic nodular growth in the portal triad that effaced adjacent hepatic parenchyma.
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