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CLINICAL RELEVANCE This study identifies key signs and symptoms of acute conjunctivitis, that when combined with a point-of-care test, can improve clinician accuracy of diagnosing adenoviral conjunctivitis. BACKGROUND Adenoviral conjunctivitis is a common ocular infection with the potential for high economic impact due to widespread outbreaks and subsequent furloughs from work and school. In this report, we describe clinical signs and participant-reported symptoms that most accurately identify polymerase chain reaction (PCR)-confirmed adenoviral conjunctivitis. METHODS Adults with 'red eye' symptoms of four days or less were enrolled. Participants rated 10 ocular symptoms from 0 (not bothersome) to 10 (very bothersome), and indicated the presence or absence of systemic flu-like symptoms. Clinicians determined the presence or absence of swollen lymph nodes and rated the severity of eight ocular signs using a 5-point scale. An immunoassay targeting adenovirus antigen was utilised for the point-of-care test, and conjunctival swab samples were obtained for subsequent adenovirus detection by PCR analyses. Univariate and multivariate logistic regression models were used to identify symptoms and signs associated with PCR-confirmed adenoviral conjunctivitis. The diagnostic accuracy of these clinical findings, and the potential benefit of incorporating point-of-care test results, was assessed by calculating areas under the receiver operating characteristic curves (AUC). RESULTS Clinician-rated bulbar conjunctival redness, participant-rated eyelid swelling and overall ocular discomfort had the best predictive value in the multivariate logistic regression model with an AUC of 0.83. The addition of the point-of-care test results to these three clinical sign/symptom scores improved diagnostic accuracy, increasing the AUC to 0.94. CONCLUSIONS Conjunctival redness severity and participant-reported eyelid swelling and overall discomfort, along with adenoviral point-of-care test results, were highly predictive in identifying individuals with PCR-confirmed adenoviral conjunctivitis. Improved diagnostic accuracy by clinicians at the initial presenting visit could prevent unnecessary work furloughs and facilitate earlier treatment decisions.

PURPOSE: To determine the change in intraocular pressure (IOP), ocular hypotensive medication use after cataract extraction in the Medication Group of the Ocular Hypertension Treatment Study (OHTS). DESIGN: Secondary analysis of randomized clinical trial data METHODS: We included 92 participants (n=149 eyes) of the OHTS Medication Group who underwent cataract surgery in at least one eye during the study, and 531 participants (n=1004 eyes) of the Medication Group who did not undergo cataract surgery. We defined the “split date” as the first study visit that cataract surgery was reported for the cataract surgery group, and the 15(th) visit in the control group to equalize the median number of visits. We then compared the two groups at visits relative to this split date. • MAIN OUTCOME MEASURES: Difference in preoperative and postoperative IOP, and number of classes of ocular hypotensive medications between the cataract and control group over a 72 month period. RESULTS: Cataract surgery significantly decreased the number of ocular hypotensive medications at all postoperative visits (mean −0.4 medications, p

The presence of eyebrow elevation in anophthalmic patients has been used as evidence to support a proprioceptive stimulus for frontalis innervation. In this study, we examined the frequency of brow elevation before and after enucleation and reviewed additional clinical findings to determine if any were associated with eyebrow position.A retrospective study was performed on 134 anophthalmic patients. Demographics, measurements, and photographs were reviewed. Reference photographs were used to subjectively grade brow position and sulcus depth.Preoperative eyebrow elevation was present in 56.2% of patients without blepharospasm from a painful eye, of who 62% had chronic visual loss. Ipsilateral ptosis (p = 0.008), deep superior sulcus (plt; 0.001), and right-sided pathology (p = 0.045) were more common in patients with brow elevation. Symmetrically elevated brows were more frequent before right than left enucleation (p = 0.05). Brow position remained stable after 61.9% of procedures. While often mild, postoperative brow elevation was seen in 31.0% of patients without preoperative elevation. Deepening of the superior sulcus was more common in patients with new relative brow elevation (p = 0.031). Anophthalmic ptosis and right-left surgical side were not associated with new postoperative brow elevation.Eyebrow elevation was often present prior to enucleation and associated with an increased occurrence of ptosis, superior sulcus deepening, and right-sided pathology. Intact vision was not needed to maintain an elevated brow. Superior sulcus deepening, but not ptosis, was more common in patients developing new postoperative brow elevation. The findings support both proprioceptive and compensatory mechanisms for eyebrow elevation.

Purpose The purpose of this study was to describe the academic performance of childhood retinoblastoma (RB) survivors. Design Retrospective cohort study. Methods Retrospective chart review of children followed in a survivorship clinic. Results A total of 73 patients with RB (median age at diagnosis: 9.97 months; range: 0.29-65.1) were followed for a median of 6.4 years (0.2-1.76). A total of 48 patients (65.8%) had unilateral RB; 43 patients (63.0%) received systemic chemotherapy; and 57 patients (78.1%) underwent enucleation. At last follow-up, 5 children (6.8%) had bilateral visual acuity (VA) Conclusions Academic difficulties in childhood RB survivors are associated with chemotherapy treatment, a risk factor independent of VA.

Significance The effectiveness of masking is rarely evaluated or reported in single- or double-masked clinical trials. Knowledge of treatment assignment by participants and clinicians can bias the assessment of treatment efficacy. Purpose This study aimed to evaluate the effectiveness of masking in a double-masked trial of 5% povidone-iodine for the treatment of adenoviral conjunctivitis. Methods The Reducing Adenoviral Patient Infected Days study is a double-masked, randomized trial comparing a one-time, in-office administration of 5% povidone-iodine with artificial tears for the treatment of adenoviral conjunctivitis. Masking was assessed by asking participants and masked clinicians at designated time points if they believed the treatment administered was povidone-iodine or artificial tears, or if they were unsure. Adequacy of masking was quantified using a modified Bang Blinding Index. Results Immediately after treatment, 34% of participants who received povidone-iodine and 69% of those who received artificial tears guessed incorrectly or were unsure of their treatment (modified Bang Indices of 0.31 and -0.38, respectively). On day 4, 38% of the povidone-iodine participants and 52% of the artificial tear participants guessed incorrectly or were unsure of their treatment (modified Bang Indices of 0.24 and -0.05, respectively), indicating adequate and ideal masking. On days 1, 4, 7, 14, and 21, masked clinicians guessed incorrectly or were unsure of treatment in 53%, 50%, 40%, 39%, and 42% among povidone-iodine participants compared with 44%, 35%, 38%, 35%, and 39% among artificial tears participants, respectively. The modified Bang Indices for clinician masking in the povidone-iodine group ranged from -0.05 to 0.25 and from 0.13 to 0.29 in the artificial tears group. Conclusions Masking of participants and clinicians was adequate. Successful masking increases confidence that subjective measurements are not biased. We recommend quantitative assessment and reporting the effectiveness of masking in ophthalmic clinical trials.

Purpose To compare the use of sizing implants versus intraoperative volume measurements for individualization of enucleation implant size, and to identify preoperative factors affecting the choice of implant. Methods In this retrospective observational cohort study, 2 implant sizing methods were compared using clinical records and photographs in 139 patients who underwent enucleation between 2007 and 2016. Results There was no difference in mean implant (p = 0.6562) or prosthetic (p = 0.1990) enophthalmos between the 2 methods, or when comparing patients with and without conjunctival-Tenons fibrosis. The incidence and severity of superior sulcus deformity was similar between the methods (p = 0.6394). Preoperative phthisis (p 20 mm were more frequently inserted in patients with a wider Hertel exophthalmometry base (80% of males >95 mm; 77% of females >97 mm). Approximately 21.0% of patients demonstrated ≥8 mm of implant enophthalmos, suggesting an undersized implant. The authors estimate that 11% of patients could have received a sphere larger than 22 mm. Conclusions Individualization of enucleation implant size can reduce the incidence of anophthalmic socket syndrome. The empirical use of sizing implants provided similar results as intraoperative volumetric measurements, when evaluated by postoperative superior sulcus depth and prosthetic or implant enophthalmos. Preoperative exophthalmometry may facilitate selection of implant size. Preexisting conjunctival-Tenon fascial fibrosis often did not limit implant size and was not associated with a higher prevalence of wound breakdown or implant exposure.

Purpose Accurate diagnosis of adenoviral conjunctivitis (Ad-Cs) is important for timely and appropriate patient management to reduce disease transmission. This study assessed the diagnostic accuracy of a commercially available point-of-care adenovirus immunoassay and determined whether its predictive accuracy is influenced by signal intensities of test result bands. Methods Point-of-care immunoassay (AdenoPlus) testing and quantitative polymerase chain reaction (qPCR) testing was performed on conjunctival swab samples obtained from eyes of 186 eligible adult participants with presumed infectious conjunctivitis and symptoms of ≤4 days. Masked observers assessed signal intensities of the immunoassay test and control bands using densitometry. Results Ad-Cs was confirmed by qPCR in 28 of the 56 eyes that tested positive on the AdenoPlus, a 50% positive predictive value (95% confidence interval [CI] = 36.9, 63.1). No adenovirus was detected by qPCR in 128 of 130 eyes that tested negative on AdenoPlus, a 98.5% negative predictive value (CI = 96.3, 100). Sensitivity and specificity were 93% (CI = 84.4, 100) and 82% (CI = 76.0, 88.1), respectively. Viral titers significantly correlated with ratio of test band signal intensities (R2 = 0.32, P = 0.002). Higher positive predictive value was associated with higher densitometry ratios (receiver operating characteristic [ROC] area = 0.71; 95% CI = 0.59, 0.83). Conclusions Densitometric analyses suggest that the diagnostic accuracy of AdenoPlus is influenced by the signal intensity of the test result bands. Visual comparison of the test band intensities by clinicians could reduce the false positive rate of point-of-care immunoassays and aid in the diagnosis of viral infections. Translational Relevance Ratiometric densitometry of point-of-care immunoassays could aid clinicians' decision making in diagnosing infectious diseases, including Ad-Cs.

To investigate the diagnostic accuracy of deep learning (DL) algorithms to detect primary open-angle glaucoma (POAG) trained on fundus photographs from the Ocular Hypertension Treatment Study (OHTS). 66,715 photographs from 3,272 eyes were used to train and test a ResNet-50 model to detect the OHTS Endpoint Committee POAG determination based on optic disc (n=287 eyes, 3,502 photographs) and/or visual field (n=198 eyes, 2,300 visual fields) changes. OHTS training, validation and testing sets were randomly determined using an 85-5-10 percentage split by subject. Three independent test sets were used to estimate the generalizability of the model: UCSD Diagnostic Innovations in Glaucoma Study (DIGS, USA), ACRIMA (Spain) and Large-scale Attention-based Glaucoma (LAG, China). The DL model achieved an AUROC (95% CI) of 0.88 (0.82, 0.92) for the overall OHTS POAG endpoint. For the OHTS endpoints based on optic disc changes or visual field changes, AUROCs were 0.91 (0.88, 0.94) and 0.86 (0.76, 0.93), respectively. False-positive rates (at 90% specificity) were higher in photographs of eyes that later developed POAG by disc or visual field (19.1%) compared to eyes that did not develop POAG (7.3%) during their OHTS follow-up. The diagnostic accuracy of the DL model developed on the OHTS optic disc endpoint applied to 3 independent datasets was lower with AUROC ranging from 0.74 to 0.79. High diagnostic accuracy of the current model suggests that DL can be used to automate the determination of POAG for clinical trials and management. In addition, the higher false-positive rate in early photographs of eyes that later developed POAG suggests that DL models detected POAG in some eyes earlier than the OHTS Endpoint Committee.

Purpose To report safety and tolerability of a one-time administration of ophthalmic 5% povidone-iodine (5% PVP-I) in a double-masked randomized trial for the treatment of adenoviral conjunctivitis (Ad-Cs). Methods Of 212 participants screened, 56 eligible participants with red eye symptoms ≤4 days and a positive adenoviral rapid immunoassay were randomized to a one-time administration of ophthalmic 5% PVP-I or preservative free artificial tears (AT). Safety was assessed by corneal fluorescein staining (baseline, immediate post-administration and Day 1) and visual acuity (VA) (baseline and Day 1). Tolerability was assessed using participant-rated overall ocular discomfort (baseline, immediately post-administration and on Day 1. Results In the 5% PVP-I group, corneal staining increased immediately post-administration but returned to baseline levels by Day 1. There was no change in VA between baseline and Day 1 in either 5% PVP-I or AT groups (p = 0.87). In the 5% PVP-I group, there was no change in participant-rated overall discomfort immediately post-administration (p = 0.78) or on day 1 (p = 0.10) compared to baseline. In the AT group, participant-rated overall discomfort was lower immediately post-administration but returned to baseline levels by Day 1. One adverse event was reported in the 5% PVP-I group on Day 1–2 that was classified as not related to treatment. Conclusion These results suggest ophthalmic 5% PVP-I used as a one-time treatment is safe and well tolerated by patients with Ad-Cs.

To explore the incidence of and potential risk factors for developing persistent low-pressure syndrome after lumbar puncture (LP) in patients with idiopathic intracranial hypertension (IIH), as measured by use of blood patches.A retrospective chart review was conducted of patients with definitively diagnosed IIH by clinical examination and LP, comparing them to patients with multiple sclerosis (MS) as controls who also received diagnostic LPs. Demographic, clinical, and radiological data were collected for each patient. The main outcome measure was the rate of post-LP blood patches in IIH patients compared with MS patients. Secondary outcome measures were the likelihood of undergoing an epidural blood patch related to age, body mass index, volume removed, opening pressure, the difference between opening and closing pressure, and the level of puncture within the IIH cohort.One hundred four IIH patients and 149 MS patients were included in the study. Among IIH patients, 12/104 (11.5%) underwent an epidural blood patch after LP as compared to 8/149 (5.4%) of the MS control patients (P = 0.086). Within the IIH population, none of the clinical or LP parameters were significantly correlated with increased risk of needing a blood patch.The incidence of low-pressure syndrome, as measured by blood patches, is similar in IIH patients and MS controls. This suggests that having elevated intracranial pressure before an LP is not protective against developing postpuncture low-pressure syndrome, contrary to common assumptions.

Purpose To determine the relationship between glaucoma severity and rate of falls, fear of falling, and avoidance of activities at-risk for falls. Design Cross-sectional study. Methods Patients with glaucoma (n = 138) 55 to 90 years of age with mild (n = 61), moderate (n = 54), or advanced (n = 23) glaucoma in the better eye based on the Glaucoma Staging System and age-matched control subjects (n = 50) were recruited from the Eye Clinics at Washington University, St. Louis, MO. Participants completed questionnaires regarding falls, the fear of falling, and the avoidance of activities at-risk for falls. Results Of the glaucoma participants, 36% reported ≥1 fall in the previous 12 months compared with 20% of control subjects (adjusted odds ratio [OR] 2.7 [95% confidence interval {CI} 1.18-6.17]; P = .018). Compared with control subjects, the mild glaucoma group trended toward a higher fall risk (adjusted OR 2.43 [95% CI 0.97-6.08]; P = .059) and the advanced group had the highest fall risk (adjusted OR 7.97 [95% CI 2.44-26.07]; P = .001). A greater risk of a high fear of falling and high avoidance of at-risk activities occurred at the moderate stage of glaucoma compared with control subjects (adjusted OR 4.66 [95% CI 1.24-17.49]; P = .023 and adjusted OR 4.49 [95% CI 1.34-15.05]; P = .015, respectively). Conclusions Patient education, interventions, and appropriate referrals to minimize falls should be considered in older adults with early glaucoma and continue with advancing disease. Minimizing a patient's fall risk may decrease their fear of falling and avoidance of at-risk activities. Reducing falls, the fear of falling, and the avoidance of at-risk activities may lower morbidity and mortality and improve emotional and social well-being of patients with glaucoma. Am J Ophthalmol 2021;221:•••–•••. © 2021 Elsevier Inc. All rights reserved.

OBJECTIVE: To test whether crowdsourced lay raters can accurately assess cataract surgical skills. DESIGN: Two-armed study: independent cross-sectional and longitudinal cohorts. SETTING: Washington University Department of Ophthalmology. PARTICIPANTS AND METHODS: Sixteen cataract surgeons with varying experience levels submitted cataract surgery videos to be graded by 5 experts and 300+ crowdworkers masked to surgeon experience. Cross-sectional study: 50 videos from surgeons ranging from first-year resident to attending physician, pooled by years of training. Longitudinal study: 28 videos obtained at regular intervals as residents progressed through 180 cases. Surgical skill was graded using the modified Objective Structured Assessment of Technical Skill (mOSATS). Main outcome measures were overall technical performance, reliability indices, and correlation between expert and crowd mean scores. RESULTS: Experts demonstrated high interrater reliability and accurately predicted training level, establishing construct validity for the modified OSATS. Crowd scores were correlated with (r = 0.865, p < 0.0001) but consistently higher than expert scores for first, second, and third-year residents (p < 0.0001, paired t-test). Longer surgery duration negatively correlated with training level (r = −0.855, p < 0.0001) and expert score (r = −0.927, p < 0.0001). The longitudinal dataset reproduced cross-sectional study findings for crowd and expert comparisons. A regression equation transforming crowd score plus video length into expert score was derived from the cross-sectional dataset (r2 = 0.92) and demonstrated excellent predictive modeling when applied to the independent longitudinal dataset (r2 = 0.80). A group of student raters who had edited the cataract videos also graded them, producing scores that more closely approximated experts than the crowd. CONCLUSIONS: Crowdsourced rankings correlated with expert scores, but were not equivalent; crowd scores overestimated technical competency, especially for novice surgeons. A novel approach of adjusting crowd scores with surgery duration generated a more accurate predictive model for surgical skill. More studies are needed before crowdsourcing can be reliably used for assessing surgical proficiency.

Background: Primary open-angle glaucoma (POAG) is one of the leading causes of irreversible blindness in the United States and worldwide. Although deep learning methods have been proposed to diagnose POAG, it remains challenging to develop a robust and explainable algorithm to facilitate the downstream diagnostic tasks automatically. Methods: We proposed a deep learning model, GlaucomaNet, with joint fusion to identify POAG from fundus photographs. GlaucomaNet consists of two neural networks to simulate the human grading process: one performing preliminary grading and the other detailed grading. An ensemble of network architectures further improved diagnostic accuracy. GlaucomaNet was evaluated on two independent datasets. The performance was measured by AUC, accuracy, precision, sensitivity, specificity, and F1-score. Findings: GlaucomaNet was trained and evaluated on two datasets: 37,339 fundus photographs from the Ocular Hypertension Treatment Study (OHTS), and 4,855 fundus photographs from the Large-scale Attention-based Glaucoma (LAG) dataset. GlaucomaNet achieved superior performance to six state-of-the-art neural networks on OHTS, with accuracy of 0.930 (standard deviation, 0.010), F1-score of 0.490 (0.033), and AUC of 0.904 (0.014). It also outperformed the baselines on the LAG dataset. Interpretations: GlaucomaNet demonstrated high accuracy with increased transparency in POAG diagnosis. It is also applicable for two well-known challenges: image data diversity and POAG only due to visual fields abnormalities. These results highlight the potential of deep learning to assist and enhance clinical POAG diagnosis. GlaucomaNet is publicly available on https://github.com/bionlplab/GlaucomaNet. Funding: This project was supported by the National Library of Medicine (4R00LM013001), the National Eye Institute, the National Center on Minority Health and Health Disparities (EY09341, EY09307) at NIH, Horncrest Foundation, the Department of Ophthalmology and Visual Sciences at Washington University, the NIH Vision Core Grant (P30EY02687), Merck Research Laboratories, Pfizer, Inc., White House Station, New Jersey, and unrestricted grants from Research to Prevent Blindness, Inc., New York, NY. Declaration of Interest: Ethical Approval: The first dataset is obtained from the Ocular Hypertension Treatment Study (OHTS). The OHTS comes from 22 centers in the United States. The study protocol was approved by an independent Institutional Review Board at each clinical center

IMPORTANCE: Automated deep learning (DL) analyses of fundus photographs potentially can reduce the cost and improve the efficiency of reading center assessment of end points in clinical trials. OBJECTIVE: To investigate the diagnostic accuracy of DL algorithms trained on fundus photographs from the Ocular Hypertension Treatment Study (OHTS) to detect primary open-angle glaucoma (POAG). DESIGN, SETTING, AND PARTICIPANTS: In this diagnostic study, 1636 OHTS participants from 22 sites with a mean (range) follow-up of 10.7 (0-14.3) years. A total of 66 715 photographs from 3272 eyes were used to train and test a ResNet-50 model to detect the OHTS Endpoint Committee POAG determination based on optic disc (287 eyes, 3502 photographs) and/or visual field (198 eyes, 2300 visual fields) changes. Three independent test sets were used to evaluate the generalizability of the model. MAIN OUTCOMES AND MEASURES: Areas under the receiver operating characteristic curve (AUROC) and sensitivities at fixed specificities were calculated to compare model performance. Evaluation of false-positive rates was used to determine whether the DL model detected POAG before the OHTS Endpoint Committee POAG determination. RESULTS: A total of 1147 participants were included in the training set (661 [57.6%] female; mean age, 57.2 years; 95% CI, 56.6-57.8), 167 in the validation set (97 [58.1%] female; mean age, 57.1 years; 95% CI, 55.6-58.7), and 322 in the test set (173 [53.7%] female; mean age, 57.2 years; 95% CI, 56.1-58.2). The DL model achieved an AUROC of 0.88 (95% CI, 0.82-0.92) for the OHTS Endpoint Committee determination of optic disc or VF changes. For the OHTS end points based on optic disc changes or visual field changes, AUROCs were 0.91 (95% CI, 0.88-0.94) and 0.86 (95% CI, 0.76-0.93), respectively. False-positive rates (at 90% specificity) were higher in photographs of eyes that later developed POAG by disc or visual field (27.5% [56 of 204]) compared with eyes that did not develop POAG (11.4% [50 of 440]) during follow-up. The diagnostic accuracy of the DL model developed on the optic disc end point applied to 3 independent data sets was lower, with AUROCs ranging from 0.74 (95% CI, 0.70-0.77) to 0.79 (95% CI, 0.78-0.81). CONCLUSIONS AND RELEVANCE: The model’s high diagnostic accuracy using OHTS photographs suggests that DL has the potential to standardize and automate POAG determination for clinical trials and management. In addition, the higher false-positive rate in early photographs of eyes that later developed POAG suggests that DL models detected POAG in some eyes earlier than the OHTS Endpoint Committee, reflecting the OHTS design that emphasized a high specificity for POAG determination by requiring a clinically significant change from baseline.

To compare the use of sizing implants versus intraoperative volume measurements for individualization of enucleation implant size, and to identify preoperative factors affecting the choice of implant.In this retrospective observational cohort study, 2 implant sizing methods were compared using clinical records and photographs in 139 patients who underwent enucleation between 2007 and 2016.There was no difference in mean implant (p = 0.6562) or prosthetic (p = 0.1990) enophthalmos between the 2 methods, or when comparing patients with and without conjunctival-Tenons fibrosis. The incidence and severity of superior sulcus deformity was similar between the methods (p = 0.6394). Preoperative phthisis (p0.0001) and intraoperative conjunctival-Tenons fibrosis (p = 0.0010) were more common in the sizing implant group. Among all study patients, mean implant size was larger in males (21.3 mm, n = 80) than females (20.7 mm, n = 59) (p = 0.0027). Implants20 mm were more frequently inserted in patients with a wider Hertel exophthalmometry base (80% of males95 mm; 77% of females97 mm). Approximately 21.0% of patients demonstrated ≥8 mm of implant enophthalmos, suggesting an undersized implant. The authors estimate that 11% of patients could have received a sphere larger than 22 mm.Individualization of enucleation implant size can reduce the incidence of anophthalmic socket syndrome. The empirical use of sizing implants provided similar results as intraoperative volumetric measurements, when evaluated by postoperative superior sulcus depth and prosthetic or implant enophthalmos. Preoperative exophthalmometry may facilitate selection of implant size. Preexisting conjunctival-Tenon fascial fibrosis often did not limit implant size and was not associated with a higher prevalence of wound breakdown or implant exposure.

PURPOSE To describe the incidence of anophthalmic ptosis, identify clinical factors associated with its development, and evaluate the effects of enucleation on eyelid mechanics. METHODS In this observational cohort study, measurements and photographs were reviewed in 139 patients who underwent enucleation between 2007 and 2016. Patient demographics, pre- and postoperative eyelid measurements, and exophthalmometry were used to assess the incidence of ptosis and effects of surgery on eyelid function. RESULTS Preoperative ptosis was common and more often present in patients with enophthalmos (p = 0.0305) or reactive blepharospasm (p < 0.0001). The incidence of new-onset ptosis and improvement of preexisting ptosis following enucleation were similar (40%). Surgical repair was performed in 7% of patients with ptosis. Contralateral levator function declined with age and was positively correlated with exophthalmometry (p < 0.0001). Anophthalmic levator function was greater with increased anterior projection of the implant (p < 0.0001) and prosthesis (p < 0.0001). Patients with larger implants had improved levator function, with (p = 0.0065) and without (p = 0.0007) the prosthesis. Superior sulcus deepening was associated with decreased levator activity, but not margin-reflex distance. CONCLUSIONS Preoperative ptosis was common, and often related to reactive blepharospasm or enophthalmos. Levator function declined with age, and correlated to greater anterior projection of the implant and prosthesis following enucleation. The surgeon can counsel patients regarding the similar likelihood (40%) of preoperative ptosis improving and new ptosis developing after enucleation. The primary factor the surgeon can modify to improve postoperative eyelid function is to maximize implant size, which is associated with greater levator activity.

Central corneal thickness influences intraocular pressure (IOP) measurement. We examined the central corneal thickness of subjects in the Ocular Hypertension Treatment Study (OHTS) and determined if central corneal thickness is related to race.Cross-sectional study.One thousand three hundred one OHTS subjects with central corneal thickness measurements.Central corneal thickness was determined with ultrasonic pachymeters of the same make and model at all clinical sites of the OHTS.Correlation of mean central corneal thickness with race, baseline IOP, refraction, age, gender, systemic hypertension, and diabetes.Mean central corneal thickness was 573.0 +/- 39.0 microm. Twenty-four percent of the OHTS subjects had central corneal thickness600 microm. Mean central corneal thickness for African American subjects (555.7 +/- 40.0 microm; n = 318) was 23 microm thinner than for white subjects (579.0 +/- 37.0 microm; P0.0001). Other factors associated with greater mean central corneal thickness were younger age, female gender, and diabetes.OHTS subjects have thicker corneas than the general population. African American subjects have thinner corneas than white subjects in the study. The effect of central corneal thickness may influence the accuracy of applanation tonometry in the diagnosis, screening, and management of patients with glaucoma and ocular hypertension.

In this paper we are interested in capturing heterogeneity in clustered or longitudinal data. Traditionally such heterogeneity is modeled by either fixed effects or random effects. In fixed effects models, the degree of freedom for the heterogeneity equals the number of clusters/subjects minus 1, which could result in less efficiency. In random effects models, the heterogeneity across different clusters/subjects is described by e.g., a random intercept with 1 parameter (for the variance of the random intercept), which could lead to oversimplification and biases (for the estimates of subject-specific effects). Our “fused effects” model stands in between these two approaches: we assume that there are unknown number of distinct levels of heterogeneity, and use the fusion penalty approach for estimation and inference. We evaluate and compare the performance of our method to the fixed and random effects models by simulation studies. We apply our method to the Ocular Hypertension Treatment Study (OHTS) to capture the heterogeneity in the progression rate of primary open-angle glaucoma of left and right eyes of different subjects.

Background Estimating correlation coefficients among outcomes is one of the most important analytical tasks in epidemiological and clinical research. Availability of multivariate longitudinal data presents a unique opportunity to assess joint evolution of outcomes over time. Bivariate linear mixed model (BLMM) provides a versatile tool with regard to assessing correlation. However, BLMMs often assume that all individuals are drawn from a single homogenous population where the individual trajectories are distributed smoothly around population average. Methods Using longitudinal mean deviation (MD) and visual acuity (VA) from the Ocular Hypertension Treatment Study (OHTS), we demonstrated strategies to better understand the correlation between multivariate longitudinal data in the presence of potential heterogeneity. Conditional correlation (i.e., marginal correlation given random effects) was calculated to describe how the association between longitudinal outcomes evolved over time within specific subpopulation. The impact of heterogeneity on correlation was also assessed by simulated data. Results There was a significant positive correlation in both random intercepts (ρ = 0.278, 95% CI: 0.121–0.420) and random slopes (ρ = 0.579, 95% CI: 0.349–0.810) between longitudinal MD and VA, and the strength of correlation constantly increased over time. However, conditional correlation and simulation studies revealed that the correlation was induced primarily by participants with rapid deteriorating MD who only accounted for a small fraction of total samples. Conclusion Conditional correlation given random effects provides a robust estimate to describe the correlation between multivariate longitudinal data in the presence of unobserved heterogeneity (NCT00000125).

Purpose: In animal models, insulin resistance without severe hyperglycemia is associated with retinopathy; however, corroborating data in humans are lacking. This study aims to investigate the prevalence of retinopathy in a population without diabetes and evaluate the association of insulin resistance and retinopathy within this group.Methods: The study population included 1914 adults age ≥40 without diabetes who were assigned to the morning, fasted group in the National Health and Nutrition Examination Survey 2005-2008, conducted by the Centers for Disease Control. Retinopathy was determined using fundus photos independently graded by a reading center and insulin resistance was determined using the homeostatic model of insulin resistance.Results: Prevalence of retinopathy in those without diabetes was survey design adjusted 9.4% (174/1914). In multivariable analyses, retinopathy was associated with insulin resistance (HOMA-IR OR: 1.09, 95% CI: 1.03, 1.16; p = .0030), male gender (OR: 1.39, 95% CI: 1.04, 1.85; p = .0267), and age (OR: 1.03, 95% CI: 1.01, 1.05; p = .0203).Conclusions: Insulin resistance in the absence of overt hyperglycemia could be an early driver of retinopathy.

PURPOSE: The origin of blood in glaucoma-related disc hemorrhages (DH) remains unknown. A prior clinic-based study of primary open-angle glaucoma (POAG)-related DH showed that they had grayscale pixel intensities more similar to blood from retinal macroaneurysms and adjacent retinal arterioles than to blood from retinal vein occlusions or adjacent retinal venules, suggesting an arterial source. Here we assessed the densitometric profile of DH from fundus photographs in the Ocular Hypertension Treatment Study (OHTS). DESIGN: Retrospective cross-sectional study of prospectively collected images. METHODS: Stereo disc photographs of 161 DH events from 83 OHTS participants (mean age (standard deviation (SD)): 65.6 (9.2) years; 46.6% female; 13.0% black race) were imported into ImageJ to measure densitometry differences (adjacent arterioles minus DH (ΔA) or venules minus DH (ΔV)). Their size as percentage of disc area, ratio of length to midpoint width, and location relative to the disc margin were also analyzed. We performed t-tests to compare ΔA and ΔV, analysis of variance to compare ΔA and ΔV across DH recurrent events, and multivariable linear regression to identify determinants of ΔA and ΔV. RESULTS: Mean (SD) ΔA and ΔV were −2.2 (8.7) and −11.4 (9.7) pixel intensity units, respectively (P

Importance Ocular hypertension is an important risk factor for the development of primary open-angle glaucoma (POAG). Data from long-term follow-up can be used to inform the management of patients with ocular hypertension. Objective To determine the cumulative incidence and severity of POAG after 20 years of follow-up among participants in the Ocular Hypertension Treatment Study. Design, Setting, and Participants Participants in the Ocular Hypertension Treatment Study were followed up from February 1994 to December 2008 in 22 clinics. Data were collected after 20 years of follow-up (from January 2016 to April 2019) or within 2 years of death. Analyses were performed from July 2019 to December 2020. Interventions From February 28, 1994, to June 2, 2002 (phase 1), participants were randomized to receive either topical ocular hypotensive medication (medication group) or close observation (observation group). From June 3, 2002, to December 30, 2008 (phase 2), both randomization groups received medication. Beginning in 2009, treatment was no longer determined by study protocol. From January 7, 2016, to April 15, 2019 (phase 3), participants received ophthalmic examinations and visual function assessments. Main Outcomes and Measures Twenty-year cumulative incidence and severity of POAG in 1 or both eyes after adjustment for exposure time. Results A total of 1636 individuals (mean [SD] age, 55.4 [9.6] years; 931 women [56.9%]; 1138 White participants [69.6%]; 407 Black/African American participants [24.9%]) were randomized in phase 1 of the clinical trial. Of those, 483 participants (29.5%) developed POAG in 1 or both eyes (unadjusted incidence). After adjusting for exposure time, the 20-year cumulative incidence of POAG in 1 or both eyes was 45.6% (95% CI, 42.3%-48.8%) among all participants, 49.3% (95% CI, 44.5%-53.8%) among participants in the observation group, and 41.9% (95% CI, 37.2%-46.3%) among participants in the medication group. The 20-year cumulative incidence of POAG was 55.2% (95% CI, 47.9%-61.5%) among Black/African American participants and 42.7% (95% CI, 38.9%-46.3%) among participants of other races. The 20-year cumulative incidence for visual field loss was 25.2% (95% CI, 22.5%-27.8%). Using a 5-factor baseline model, the cumulative incidence of POAG among participants in the low-, medium-, and high-risk tertiles was 31.7% (95% CI, 26.4%-36.6%), 47.6% (95% CI, 41.6%-53.0%), and 59.8% (95% CI, 53.1%-65.5%), respectively. Conclusions and Relevance In this study, only one-fourth of participants in the Ocular Hypertension Treatment Study developed visual field loss in either eye over long-term follow-up. This information, together with a prediction model, may help clinicians and patients make informed personalized decisions about the management of ocular hypertension. Trial Registration ClinicalTrials.gov Identifier:NCT00000125.

Purpose Primary open-angle glaucoma (POAG) is a major cause of blindness and visual disability. Several genetic risk factors for POAG and optic nerve features have been identified. We measured the relative risk for glaucoma that these factors contribute to participants in the Ocular Hypertension Treatment Study (OHTS). Design Comparative series. Participants One thousand fifty-seven of 1636 participants (65%) of the OHTS were enrolled in this genetics ancillary study. Methods Samples of DNA were available from 1057 OHTS participants. Of these, 209 developed POAG (cases) and 848 did not develop glaucoma (controls) between 1994 and 2009. The frequencies of 13 risk alleles previously associated with POAG or with optic disc features in other cohorts were compared between POAG cases and controls in the OHTS cohort using analyses of variance. The 2 largest subgroups, non-Hispanic whites (n = 752; 70.7%) and blacks (n = 249, 23.7%), also were analyzed separately. The probability of glaucoma developing over the course of the OHTS was compared between participants stratified for transmembrane and coiled-coil domains 1 ( TMCO1 ) risk alleles using Kaplan-Meier and Cox proportional hazards analyses. Main Outcome Measures Association of POAG with known genetic factors. Results No association was detected between the known POAG risk alleles when the OHTS cohort was examined as a whole. However, in the subgroup of non-Hispanic whites, allele frequencies at the TMCO1 locus were statistically different between cases and controls ( P = 0.00028). By 13 years, non-Hispanic white participants with TMCO1 risk alleles had a 12% higher cumulative frequency of glaucoma developing than participants with no TMCO1 risk alleles. Moreover, the Cox proportional hazard analysis demonstrated that TMCO1 alleles increased relative risk comparable with that of some previously analyzed clinical measures (i.e., intraocular pressure). Conclusions The size of the OHTS cohort and its composition of 2 large racial subgroups may limit its power to detect some glaucoma risk factors. However, TMCO1 genotype was found to increase the risk of glaucoma developing among non-Hispanic whites, the largest racial subgroup in the OHTS cohort, at a magnitude similar to clinical predictors of disease that long have been associated with glaucoma.

Date Presented 03/28/20 This study identified compensatory strategies used by individuals with glaucoma who drove safely and those who failed an on-road driving test. Participants completed vision tests, a compensatory driving strategies questionnaire, and an on-road driving assessment. Preliminary results indicate that individuals with glaucoma who failed the on-road assessment modified their driving, used selected vehicular technology more frequently, and were older than those who passed. Primary Author and Speaker: Monica Perlmutter Additional Authors and Speakers: Peggy Barco Contributing Authors: Anjali Bhorade, Tracy Raben, David Carr, Mae Gordon, Brad Wilson

Importance The contribution of long-term intraocular pressure (IOP) variability to the development of primary open-angle glaucoma is still controversial. Objective To assess whether long-term IOP variability data improve a prediction model for the development of primary open-angle glaucoma (POAG) in individuals with untreated ocular hypertension. Design, Setting, and Participants This post hoc secondary analysis of 2 randomized clinical trials included data from 709 of 819 participants in the observation group of the Ocular Hypertension Treatment Study (OHTS) followed up from February 28, 1994, to June 1, 2002, and 397 of 500 participants in the placebo group of the European Glaucoma Prevention Study (EGPS) followed up from January 1, 1997, to September 30, 2003. Data analyses were completed between January 1, 2019, and March 15, 2020. Exposures The original prediction model for the development of POAG included the following baseline factors: age, IOP, central corneal thickness, vertical cup-disc ratio, and pattern SD. This analysis tested whether substitution of baseline IOP with mean follow-up IOP, SD of IOP, maximum IOP, range of IOP, or coefficient of variation IOP would improve predictive accuracy. Main Outcomes and Measures The C statistic was used to compare the predictive accuracy of multivariable landmark Cox proportional hazards regression models for the development of POAG. Results Data from the OHTS consisted of 97 POAG end points from 709 of 819 participants (416 [58.7%] women; 177 [25.0%] African American and 490 [69.1%] white; mean [SD] age, 55.7 [9.59] years; median [range] follow-up, 6.9 [0.96-8.15] years). Data from the EGPS consisted of 44 POAG end points from 397 of 500 participants in the placebo group (201 [50.1%] women; 397 [100%] white; mean [SD] age, 57.8 [9.76] years; median [range] follow-up, 4.9 [1.45-5.76] years). The C statistic for the original prediction model was 0.741. When a measure of follow-up IOP was substituted for baseline IOP in this prediction model, the C statistics were as follows: mean follow-up IOP, 0.784; maximum IOP, 0.781; SD of IOP, 0.745; range of IOP, 0.741; and coefficient of variation IOP, 0.729. The C statistics in the EGPS were similarly ordered. No measure of IOP variability, when added to the prediction model that included mean follow-up IOP, age, central corneal thickness, vertical cup-disc ratio, and pattern SD, increased the C statistic by more than 0.007 in either cohort. Conclusions and Relevance Evidence from the OHTS and the EGPS suggests that long-term variability does not add substantial explanatory power to the prediction model as to which individuals with untreated ocular hypertension will develop POAG.

Background/aimsWe wished to determine whether the pupillary light reaction can differentiate preclinical Alzheimer’s disease (AD) subjects from normal ageing controls. We performed a prospective study evaluating the pupillary light reaction in a cohort of well-characterised subjects with preclinical AD versus normal ageing controls.MethodsWe recruited 57 subjects from our institution’s Memory and Aging Project, part of our Alzheimer’s Disease Research Center. All subjects completed PET-PiB imaging, cerebrospinal fluid analysis and at least 1 neuropsychiatric assessment after their baseline assessment. All participants were assigned a clinical dementia rating and underwent a complete neuro-ophthalmic examination. Participants were divided into a dementia biomarker+ (preclinical AD) and biomarker– (normal ageing) group based on preclinical risk for Alzheimer’s dementia. Pupillometry measurements were performed by using the NeurOptics PLR-200 Pupillometer.ResultsA total of 57 subjects were recruited with 24 dementia biomarker+ and 33 dementia biomarker- individuals. A variety of pupil flash response (PLR) parameters were assessed. Comparisons between groups were analysed using generalised estimating equations. None of the pupillary parameters showed a significant difference between groups.ConclusionsWe found no significant differences in PLR between preclinical AD subjects and normal ageing controls. This suggests that the disease effect on the PLR may be small and difficult to detect at the earliest stages of the disease. Future studies could include larger sample size and chromatic pupillometry.

Purpose To assess the impact of a masked Endpoint Committee on estimates of the incidence of primary open-angle glaucoma (POAG) treatment efficacy and statistical power of the Ocular Hypertension Treatment Study-Phase 1, 1994-2002 (OHTS-1). Design Retrospective interrater reliability analysis of endpoint attribution by the Endpoint Committee. Methods After study closeout, we recalculated estimates of endpoint incidence, treatment efficacy, and statistical power using all-cause endpoints and POAG endpoints. To avoid bias, only the first endpoint per participant is included in this report. Results The Endpoint Committee reviewed 267 first endpoints from 1636 participants. The Endpoint Committee attributed 58% (155 of 267) of the endpoints to POAG. The incidence of all-cause endpoints vs POAG endpoints was 19.5% and 13.2%, respectively, in the observation group and 13.1% and 5.8%, respectively, in the medication group. Treatment effect for all-cause endpoints was a 33% reduction in risk (relative risk = 0.67, 95% confidence interval [CI] of 0.54-0.84) and a 56% reduction in risk for POAG endpoints (relative risk = 0.44, 95% CI of 0.31-0.61). Post hoc statistical power for detecting treatment effect was 0.94 for all-cause endpoints and 0.99 for POAG endpoints. Conclusion Endpoint Committee adjudication of endpoints improved POAG incidence estimates, increased statistical power, and increased calculated treatment effect by 23%. An Endpoint Committee should be considered in therapeutic trials when common ocular and systemic comorbidities, other than the target condition, could compromise study results.

PURPOSE: To utilize results from the Ocular Hypertension Study that can aid patients and clinicians to make evidence based decisions about the management of ocular hypertension. DESIGN: 1636 participants with ocular hypertension were randomized to treatment with topical ocular hypotensive treatment or close observation. The goal of treatment was a 20% reduction in intraocular pressure and an intraocular pressure of ≤ 24 mmHg. After a mean of 7.5 years, participants in the observation group also received treatment. Visual field tests that were performed twice a year and optic disc photographs once a year. RESULTS: At 60 months, the cumulative frequency of developing POAG was 4.4% in the medication group and 9.5% in the observation group (hazard ratio for medication, 0.40; 95% CI, 0.27–0.59; P

This case-control study uses data from the British Columbia Ministry of Health databases to assess the effect of recurring intravitreous bevacizumab injections with the need for glaucoma surgery.

To determine the cumulative incidence of optic disc hemorrhage (ODH) before and after development of primary open-angle glaucoma (POAG); determine the prognostic significance of ODH for the development of POAG; and identify predictive factors for ODH.Prospective cohort study.ODHs were evaluated in 3236 eyes of 1618 Ocular Hypertension Treatment Study (OHTS) participants annually using stereoscopic optic disc photographs. The incidence of ODH before and after the development of POAG, the risk of ODH for POAG, and risk factors for ODH were determined using a multivariate proportional hazards regression model.After a median follow-up of 13 years, 1 or more ODHs were detected in 179 eyes of 169 participants. The incidence of ODH was 0.5% per year during an average of 13 years before the development of POAG and 1.2% per year during an average of 6 years after the development of POAG. The cumulative incidence of POAG in eyes with ODH was 25.6% compared with 12.9% in eyes without ODH. The occurrence of an ODH increased the risk of developing POAG 2.6-fold in the multivariate analysis (95% confidence interval, 1.7-4.0; P.0001). Randomization to the observation group, older age, thinner central corneal thickness, larger vertical cup-to-disc ratio, higher intraocular pressure, and self-reported black race were identified as risk factors for ODH.ODH is an independent predictive factor for the development of POAG in patients with ocular hypertension (OHT) and the predictive factors for ODH are very similar to those for POAG in OHT patients.

To explore the relationship between diffusion-weighted magnetic resonance imaging (DWI) hyperintensity of the optic nerve head (ONH) and papilledema grade in patients with idiopathic intracranial hypertension (IIH).A retrospective chart review was conducted of patients with definitively diagnosed IIH by clinical examination and visual field (VF) analysis who underwent orbital magnetic resonance imaging (MRI) within 4 weeks of diagnosis. A neuroradiologist masked to the diagnosis assessed the results of DWI for each eye independently and graded the signal intensity of the ONH into none, mild, and prominent categories. DWI grading was compared with papilledema grade and visual field mean deviation (VFMD) by Spearman rank correlation analysis and t-tests.Forty-two patients were included in the study. A statistically significant difference (P = 0.0195) was found between papilledema grade and patients with prominent DWI findings (n = 16; mean papilledema grade 3.75 ± 1.25) vs mild or no ONH hyperintensity (n = 26; mean papilledema grade 2.79 ± 1.24) at the time of initial diagnosis. DWI hyperintensity of the ONH at diagnosis was also found to be significantly correlated with the degree of papilledema at follow-up (ρ = 0.39, P = 0.0183) but not with VFMD.We found a significant correlation between the severity of papilledema and ONH hyperintensity on DWI in patients with IIH but not with VF loss or other visual parameters. These findings may offer insight into the pathophysiology of papilledema in IIH and provide a surrogate marker for the presence and severity of papilledema.

Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04).Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child's academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students' mean age was 9.4 years (range: 5-15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia.

Nanoparticles offer new options for medical diagnosis and therapeutics with their capacity to specifically target cells and tissues with imaging agents and/or drug payloads. The unique physical aspects of nanoparticles present new challenges for this promising technology. Studies indicate that nanoparticles often elicit moderate to severe complement activation. Using human in vitro assays that corroborated the mouse in vivo results we previously presented mechanistic studies that define the pathway and key components involved in modulating complement interactions with several gadolinium-functionalized perfluorocarbon nanoparticles (PFOB). Here we employ a modified in vitro hemolysis-based assay developed in conjunction with the mouse in vivo model to broaden our analysis to include PFOBs of varying size, charge and surface chemistry and examine the variations in nanoparticle-mediated complement activity between individuals. This approach may provide the tools for an in-depth structure-activity relationship study that will guide the eventual development of biocompatible nanoparticles.Unique physical aspects of nanoparticles may lead to moderate to severe complement activation in vivo, which represents a challenge to clinical applicability. In order to guide the eventual development of biocompatible nanoparticles, this team of authors report a modified in vitro hemolysis-based assay developed in conjunction with their previously presented mouse model to enable in-depth structure-activity relationship studies.

Importance Techniques that properly identify patients in whom ocular hypertension (OHTN) is likely to progress to open-angle glaucoma can assist clinicians with deciding on the frequency of monitoring and the potential benefit of early treatment. Objective To test whether Kalman filtering (KF), a machine learning technique, can accurately forecast mean deviation (MD), pattern standard deviation, and intraocular pressure values 5 years into the future for patients with OHTN. Design, Setting, and Participants This cohort study was a secondary analysis of data from patients with OHTN from the Ocular Hypertension Treatment Study, performed between February 1994 and March 2009. Patients underwent tonometry and perimetry every 6 months for up to 15 years. A KF (KF-OHTN) model was trained, validated, and tested to assess how well it could forecast MD, pattern standard deviation, and intraocular pressure at up to 5 years, and the forecasts were compared with results from the actual trial. Kalman filtering for OHTN was compared with a previously developed KF for patients with high-tension glaucoma (KF-HTG) and 3 traditional forecasting algorithms. Statistical analysis for the present study was performed between May 2018 and May 2019. Main Outcomes and Measures Prediction error and root-mean-square error at 12, 24, 36, 48, and 60 months for MD, pattern standard deviation, and intraocular pressure. Results Among 1407 eligible patients (2806 eyes), 809 (57.5%) were female and the mean (SD) age at baseline was 57.5 (9.6) years. For 2124 eyes with sufficient measurements, KF-OHTN forecast MD values 60 months into the future within 0.5 dB of the actual value for 696 eyes (32.8%), 1.0 dB for 1295 eyes (61.0%), and 2.5 dB for 1980 eyes (93.2%). Among the 5 forecasting algorithms tested, KF-OHTN achieved the lowest root-mean-square error (1.72 vs 1.85-4.28) for MD values 60 months into the future. For the subset of eyes that progressed to open-angle glaucoma, KF-OHTN and KF-HTG forecast MD values 60 months into the future within 1 dB of the actual value for 30 eyes (68.2%; 95% CI, 54.4%-82.0%) and achieved the lowest root-mean-square error among all models. Conclusions and Relevance These findings suggest that machine learning algorithms such as KF can accurately forecast MD, pattern standard deviation, and intraocular pressure 5 years into the future for many patients with OHTN. These algorithms may aid clinicians in managing OHTN in their patients.

Purpose Neuroretinopathy is increasingly being recognized as an independent cause of vision loss in diabetes. Visual field loss, as detected by frequency doubling technology (FDT)-based visual perimetry, is a sign of neuroretinopathy and occurs in early stages of diabetic retinopathy (DR). Here, we hypothesized that FDT visual field testing could identify patients with diabetic neuroretinopathy in the absence of clinically detectable microvascular DR. Methods All National Health and Nutrition Examination Survey (NHANES) 2005–2008 participants receiving fundus photography and visual field screening by FDT were included in this study. Participants with self-reported glaucoma, use of glaucoma medications, or determination of glaucoma based on disk features were excluded. Visual fields were screened using FDT protocol in which participants underwent a 19-subfield suprathreshold test. Results Patients with diabetes but no DR were more likely to have ≥1 subfield defects at 5%, 2%, and 1% probability levels than patients without diabetes (41.3% vs. 28.6%; 27.4% vs. 17.5%; 15.9% vs. 9.4%; all P < 0.0008). Multivariable regression showed that each additional glycated hemoglobin % (HbA1c) was associated with 19% greater odds of having ≥1 visual subfield defects in those with diabetes without DR (odds ratio: 1.19, 95% confidence interval: 1.07–1.33; P = 0.0020). Conclusions Patients with diabetes have visual field defects in the absence of clinically detectable DR, suggesting neuroretinopathy precedes classical microvascular disease. These defects become more frequent with the onset of visible retinopathy and worsen as the retinopathy becomes more severe. Longitudinal studies are required to understand the pathogenesis of diabetic neuroretinopathy in relation to classic DR.

Detecting silent cerebral infarcts on magnetic resonance images (MRIs) in children with sickle cell anemia is challenging, yet reproducibility of readings has not been examined in this population. We evaluated consensus rating, inter-, and intra-grader agreement associated with detecting silent cerebral infarct on screening MRI in the Silent Infarct Transfusion Trial. Three neuroradiologists provided consensus decisions for 1073 MRIs. A random sample of 53 scans was reanalyzed in blinded fashion. Agreement between first and second consensus ratings was substantial (κ = 0.70, P < .0001), as was overall intergrader agreement (κ = 0.76, P < .0001). In the test-retest sample, intragrader agreement ranged from κ of 0.57 to 0.76. Consensus decisions were more concordant when MRIs contained more than one larger lesions. Routine use of MRI to screen for silent cerebral infarcts in the research setting is reproducible in sickle cell anemia and agreement among neuroradiologists is sufficient.

OBJECTIVE. The goal was to develop an objective, comprehensive, near-task home lighting assessment for older adults with low vision. METHOD. A home lighting assessment was developed and tested with older adults with low vision. Interrater and test–retest reliability studies were conducted. Clinical utility was assessed by occupational therapists with expertise in low vision rehabilitation. RESULTS. Interrater reliability was high (intraclass correlation coefficient [ICC] = .83–1.0). Test–retest reliability was moderate (ICC = .67). Responses to a Clinical Utility Feedback Form developed for this study indicated that the Home Environment Lighting Assessment (HELA) has strong clinical utility. CONCLUSION. The HELA provides a structured tool to describe the quantitative and qualitative aspects of home lighting environments where near tasks are performed and can be used to plan lighting interventions. The HELA has the potential to affect assessment and intervention practices of rehabilitation professionals in the area of low vision and improve near-task performance of people with low vision.

� PURPOSE: To compare rates of topographic change in ocular hypertensive eyes that develop primary open-angle glaucoma (POAG) compared to eyes that do not, and to identify factors that influence the rate of change. � DESIGN: Longitudinal, randomized clinical trial. � METHODS: Four hundred forty-one participants (832 eyes) in the Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study were included. POAG was defined as repeatable visual field, photography-based optic disc changes, or both. The rate of topographic change in the 52 participants (66 eyes) who developed POAG was compared with that of participants who did not develop POAG using multivariable mixed effects models. � RESULTS: In both univariate and multivariate analyses, the rate of rim area loss was significantly faster in eyes in which POAG developed than in eyes in which it did not (univariate mean, L0.0131 mm 2 /year and L0.0026 mm 2 /year, respectively). The significantly faster rate of rim area loss in black persons found in the univariateanalysisdidnotremainsignificantwhenbaseline disc area was included in the model. In multivariate analyses, the rate of rim area loss and other topographic parameters also was significantly faster in eyes with worse baseline visual field pattern standard deviation and higher intraocular pressure during follow-up. Moreover, a significant rate of rim area loss was detected in eyes in which POAG did not develop (P < .0001). The rate of rim area loss in eyes with an optic disc POAG endpoint was significantly faster than in those with a visual field POAG endpoint. � CONCLUSIONS: The rate of rim area loss is approximately 5 times faster in eyes in which POAG developed compared with eyes in which it did not. These results suggest that measuring the rate of structural change can provide important information for the clinical management of ocular hypertensive patients. Additional follow-up is needed to determine whether the statistically significant change in the eyes in which POAG did not develop represents normal aging or glaucomatous change not detected by conventional methods. (Am J Ophthalmol 2013;155:971‐982. 2013 by Elsevier Inc. All rights reserved.)

Glaucoma is the second leading cause of blindness worldwide. Physicians often use surrogate endpoints to monitor the progression of glaucomatous neurodegeneration. These approaches are limited in their ability to quantify disease severity and progression due to inherent subjectivity, unreliability, and limitations of normative databases. Therefore, there is a critical need to identify specific molecular markers that predict or measure glaucomatous neurodegeneration. Here, we demonstrate that growth differentiation factor 15 (GDF15) is associated with retinal ganglion cell death. Gdf15 expression in the retina is specifically increased after acute injury to retinal ganglion cell axons and in a murine chronic glaucoma model. We also demonstrate that the ganglion cell layer may be one of the sources of secreted GDF15 and that GDF15 diffuses to and can be detected in aqueous humor (AH). In validating these findings in human patients with glaucoma, we find not only that GDF15 is increased in AH of patients with primary open angle glaucoma (POAG), but also that elevated GDF15 levels are significantly associated with worse functional outcomes in glaucoma patients, as measured by visual field testing. Thus, GDF15 maybe a reliable metric of glaucomatous neurodegeneration, although further prospective validation studies will be necessary to determine if GDF15 can be used in clinical practice.

Papilloedema is a key clinical finding in the diagnosis of idiopathic intracranial hypertension (IIH). However, newly proposed criteria allow diagnosis without papilloedema only if certain neuroimaging features are present. It is currently unclear if these findings persist upon resolution of papilloedema and IIH. A retrospective chart review identified three groups of patients (six per group) who had received orbital imaging within 4 weeks of fundoscopic examination: (1) IIH patients without active papilloedema, (2) IIH patients with active papilloedema, and (3) patients with no history of IIH or papilloedema. All magnetic resonance imaging (MRI) scans were graded by a neuroradiologist who was blinded to clinical status. Neuroimaging features were compared by using the Kruskal-Wallis one-way analysis of variance. Measurements of sellar and optic nerve configuration showed a statistical trend with papilloedema status. For the control group versus the active papilloedema group, the values were 0.0597 and 0.0621, respectively. For the control group versus the resolved papilloedema group, the values were 0.0485 and 0.0512, respectively. However, globe and sellar p values for the resolved papilloedema group versus the active papilloedema group were 1.000 and 0.6023, respectively, and not significant. Sellar and globe configuration suggest that a statistical trend for persistence after papilloedema has resolved and intracranial pressure (ICP) has normalised. Careful clinical correlation and fundus examination are essential because some of these neuroimaging features can be seen in normal patients and those with resolved IIH, and their presence on MRI may not necessarily indicate active disease or elevated ICP.

Purpose To compare on-road driving performance of patients with moderate or advanced glaucoma to controls and evaluate factors associated with unsafe driving. Design Case-control pilot study. Methods A consecutive sample of 21 patients with bilateral moderate or advanced glaucoma from Washington University, St Louis, Missouri and 38 community-dwelling controls were enrolled. Participants, aged 55–90 years, underwent a comprehensive clinical evaluation by a trained occupational therapist and an on-road driving evaluation by a masked driver rehabilitation specialist. Overall driving performance of pass vs marginal/fail and number of wheel and/or brake interventions were recorded. Results Fifty-two percent of glaucoma participants scored a marginal/fail compared to 21% of controls (odds ratio [OR], 4.1; 95% CI, 1.30–13.14; P = .02). Glaucoma participants had a higher risk of wheel interventions than controls (OR, 4.67; 95% CI, 1.03–21.17; P = .046). There were no differences detected between glaucoma participants who scored a pass vs marginal/fail for visual field mean deviation of the better ( P = .62) or worse ( P = .88) eye, binocular distance ( P = .15) or near ( P = .23) visual acuity, contrast sensitivity ( P = .28), or glare ( P = .88). However, glaucoma participants with a marginal/fail score performed worse on Trail Making Tests A ( P = .03) and B ( P = .05), right-sided Jamar grip strength ( P = .02), Rapid Pace Walk ( P = .03), Braking Response Time ( P = .03), and identifying traffic signs ( P = .05). Conclusions Patients with bilateral moderate or advanced glaucoma are at risk for unsafe driving—particularly those with impairments on psychometric and mobility tests. A comprehensive clinical assessment and on-road driving evaluation is recommended to effectively evaluate driving safety of these patients.

Author(s): Liu, Yutao; Bailey, Jessica Cooke; Helwa, Inas; Dismuke, W Michael; Cai, Jingwen; Drewry, Michelle; Brilliant, Murray H; Budenz, Donald L; Christen, William G; Chasman, Daniel I; Fingert, John H; Gaasterland, Douglas; Gaasterland, Terry; Gordon, Mae O; Igo, Robert P; Kang, Jae H; Kass, Michael A; Kraft, Peter; Lee, Richard K; Lichter, Paul; Moroi, Sayoko E; Realini, Anthony; Richards, Julia E; Ritch, Robert; Schuman, Joel S; Scott, William K; Singh, Kuldev; Sit, Arthur J; Song, Yeunjoo E; Vollrath, Douglas; Weinreb, Robert; Medeiros, Felipe; Wollstein, Gadi; Zack, Donald J; Zhang, Kang; Pericak-Vance, Margaret A; Gonzalez, Pedro; Stamer, W Daniel; Kuchtey, John; Kuchtey, Rachel W; Allingham, R Rand; Hauser, Michael A; Pasquale, Louis R; Haines, Jonathan L; Wiggs, Janey L | Abstract: PurposeNoncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG).MethodsUsing the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls.ResultsOnly rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment.ConclusionsOur integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

Background Patients with neuromyelitis optica (NMO) and multiple sclerosis (MS) both can present with acute optic neuritis (ON), while differing considerably in their prognosis and management. The clinical course, serologic testing results, and brain and spinal cord imaging of these diseases have been well documented. The purpose of this study was to look systematically for any differences in the imaging appearance of the optic nerve in NMO and MS-related ON. Methods Magnetic resonance imaging (MRI) of brain and orbits obtained within 6 weeks of acute ON in patients with securely diagnosed NMO (n = 6) and MS (n = 11) were retrospectively analyzed by a neuroradiologist masked to the clinical diagnosis. Standardized scoring system was used to assess and analyze the extent and nature of optic pathway involvement. Results No significant differences were observed in the presence, degree, or the type of signal alteration and contrast enhancement of the affected nerve segments between NMO and MS groups. There was a trend toward more posterior involvement of the optic nerve in the NMO group with chiasmatic enhancement exclusively seen in NMO patients. Conclusion We found a higher propensity of NMO-related ON to affect more posterior parts of the optic nerve, including chiasm, and have simultaneous bilateral disease. Further study with larger sample sizes is needed.

To determine the change in intraocular pressure (IOP) after cataract extraction in the observation group of the Ocular Hypertension Treatment Study.Comparative case series.Forty-two participants (63 eyes) who underwent cataract surgery in at least 1 eye during the study and a control group of 743 participants (743 eyes) who did not undergo cataract surgery.We defined the "split date" as the study visit date at which cataract surgery was reported in the cataract surgery group and a corresponding date in the control group. Preoperative IOP was defined as the mean IOP of up to 3 visits before the split date. Postoperative IOP was the mean IOP of up to 3 visits including the split date (0, 6, and 12 months' with "0 months" equaling the split date). In both groups, we censored data after initiation of ocular hypotensive medication or glaucoma surgery of any kind.Difference in preoperative and postoperative IOP.In the cataract group, postoperative IOP was significantly lower than the preoperative IOP (19.8 ± 3.2 mmHg vs. 23.9 ± 3.2 mmHg; P0.001). The postoperative IOP remained lower than the preoperative IOP for at least 36 months. The average decrease in postoperative IOP from preoperative IOP was 16.5%, and 39.7% of eyes had postoperative IOP ≥ 20% below preoperative IOP. A greater reduction in postoperative IOP occurred in the eyes with the highest preoperative IOP. In the control group, the corresponding mean IOPs were 23.8 ± 3.6 before the split date and 23.4 ± 3.9 after the split date.Cataract surgery decreases IOP in patients with ocular hypertension over a long period of time.