Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

Repeatability of a Virtual Reality Headset Perimeter in Glaucoma and Ocular Hypertensive Patients.

Purpose: The VisuALL S is an automated, static threshold, virtual reality-based perimeter for mobile evaluation of the visual field. We examined same-day and 3-month repeatability. Methods: Adult participants with a diagnosis of glaucoma or ocular hypertension underwent two VisuALL 24-2 Normal T- Full threshold strategy tests at baseline and one additional exam at 3 months for each eligible eye. Spearman, intraclass correlation coefficients (ICCs), and Bland-Altman plots were used to assess the correlation of individual point sensitivities and mean deviation (MD) among three tests. Results: Eighty-eight eyes (44 participants) were included. Average age was 68.1 ± 14.3 years, and 60.7% were male. VisuALL MD was highly correlated between tests (intravisit: r = 0.89, intervisit: r = 0.82; P < 0.001 for both). Bland-Altman analysis showed an average difference in intravisit MD of -0.67 dB (95% confidence interval [CI], -6.04 to 4.71 dB) and -0.15 dB (95% CI, -8.04 to 7.73 dB) for intervisit exams. Eight-five percent of pointwise intravisit ICCs were above 0.75 (range, 0.63 to 0.93), and 65% of pointwise intervisit ICCs were above 0.75 (range, 0.55 to 0.91). Conclusions: VisuALL demonstrated high correlation of MD between tests and good repeatability for individual point sensitivities among three tests in 3 months, except at the points around the blind spot and superiorly. Translational Relevance: The preliminary reproducibility results for VisuALL are encouraging. Its portable design makes it a potentially useful tool for patients with glaucoma, enabling more frequent assessments both at home and in clinical settings.

Report From the 2022 Mary Tyler Moore Vision Initiative Diabetic Retinal Disease Clinical Endpoints Workshop.

The Mary Tyler Moore Vision Initiative Diabetic Retinal Disease (DRD) Clinical Endpoints Workshop was held on October 22, 2022 to accelerate progress toward establishment of useful clinical and research endpoints and development of new therapeutics that have important relevance across the full spectrum of DRD pathology. More than 90 patient representatives, clinicians, scientists, funding and regulatory agencies, diagnostic, therapeutic and biotech industry representatives discussed the needs for new diagnostic and therapeutic approaches to prevent and restore retinal neurovascular unit integrity. Phase I of the MTM Vision Initiative plans, notably updating the DRD staging system and severity scale, establishing a human ocular biorepository and resource, and clinical endpoints and biomarker development and validation, was emphasized.

Participant Experience Using Novel Perimetry Tests to Monitor Glaucoma Progression.

PRCIS: Participant surveys taken after using tablet-based and smart visual function analyzer (SVFA) perimetry tests suggest that patients may prefer novel perimetry tests over traditional visual field machines. PURPOSE: Compare patient experience using the IMOvifa SVFA and the tablet-based Melbourne Rapid Fields visual field (VF) tests to the Humphrey Field 24-2 Swedish Interactive Threshold Algorithm Standard. PATIENTS AND METHODS: Prospective observational cohort study on adult participants with diagnoses of glaucoma suspect, ocular hypertension, or glaucoma. Participants attended 2 study visits ~3 months apart. During the first visit, participants were trained to use the 2 novel perimeters, took 1 test on both new devices and the Humphrey Field Analyzer, then were surveyed. Participants received tablets and performed weekly tablet VF tests at home between study visits. At the final study visit, participants re-took the VF tests and completed the same surveys. RESULTS: Eighty-one participants were surveyed twice. At the baseline survey, participants preferred the SVFA (71.7%) and tablet tests (69.2%) over the Humphrey VF. Most were willing to perform weekly monitoring at home on the SVFA (69.1%) and tablet (75.4%). Participants generally had a "very good" overall experience when testing on the SVFA (71.6%) and tablet (90.1%). At the final visit, fewer participants were willing to test on the tablet daily (23.5% to 9.9%; P = 0.02 for change) and more were willing to test monthly (18.5% to 33.3%; P = 0.03 for change). CONCLUSION: Users reported a preference for novel VF devices. Overall participant experience using these devices was positive, supporting the feasibility of home monitoring of VFs from an experience perspective.

Comparison of Perimetric Outcomes from a Tablet Perimeter, Smart Visual Function Analyzer, and Humphrey Field Analyzer.

PURPOSE: The tablet-based Melbourne Rapid Fields (MRF) visual field (VF) test and the IMOvifa Smart Visual Function Analyzer (SVFA) are portable perimeters that may allow for at-home monitoring and more frequent testing. We compared tablet and SVFA results with outputs from the Humphrey Field Analyzer (HFA) 24-2 Swedish Interactive Threshold Algorithm Standard program. DESIGN: Observational cross-sectional study. SUBJECTS: Adult participants with a diagnosis of glaucoma, suspected glaucoma, or ocular hypertension seen in the Massachusetts Eye and Ear glaucoma clinic were enrolled. All participants were reliable and experienced HFA testers. METHODS: Participants were tested with the SVFA and HFA. The study staff also trained participants on the MRF tablet with instructions to take weekly tests at home for 3 months. Visual field results from the 3 devices were compared. MAIN OUTCOME MEASURES: Mean deviation (MD), pattern standard deviation (PSD), reliability parameters, and point sensitivity. RESULTS: Overall, 79 participants (133 eyes) with a mean age of 61 ± 13 years (range, 26-79 years) were included; 59% of the participants were female, and the mean HFA MD was -2.7 ± 3.9 dB. The global indices of MD and PSD did not significantly vary between HFA and the 2 novel devices, except that the tablet VF reported a 0.6 dB higher PSD compared with HFA. However, tablet and SVFA sensitivities significantly differed from those of the HFA at 36 and 39 locations, respectively, out of 52 locations. Relative to HFA, the tablet overestimated light sensitivity in the nasal field while underestimating the temporal field. The SVFA generally underestimated light sensitivity, but its results were more similar to HFA results compared with the tablet. CONCLUSIONS: Although average MD values from the 2 novel devices suggest that they provide similar results to the HFA, point-by-point comparisons highlight notable deviations. Differences in specific point sensitivity values were significant, especially between the tablet and the other 2 devices. These differences may in part be explained by differences in the devices' normative databases as well as how MD is calculated. However, the tablet had substantial differences based on location, indicating that the tablet design itself may be responsible for differences in local sensitivities. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Visual Field Prediction: Evaluating the Clinical Relevance of Deep Learning Models.

Purpose: Two novel deep learning methods using a convolutional neural network (CNN) and a recurrent neural network (RNN) have recently been developed to forecast future visual fields (VFs). Although the original evaluations of these models focused on overall accuracy, it was not assessed whether they can accurately identify patients with progressive glaucomatous vision loss to aid clinicians in preventing further decline. We evaluated these 2 prediction models for potential biases in overestimating or underestimating VF changes over time. Design: Retrospective observational cohort study. Participants: All available and reliable Swedish Interactive Thresholding Algorithm Standard 24-2 VFs from Massachusetts Eye and Ear Glaucoma Service collected between 1999 and 2020 were extracted. Because of the methods' respective needs, the CNN data set included 54 373 samples from 7472 patients, and the RNN data set included 24 430 samples from 1809 patients. Methods: The CNN and RNN methods were reimplemented. A fivefold cross-validation procedure was performed on each model, and pointwise mean absolute error (PMAE) was used to measure prediction accuracy. Test data were stratified into categories based on the severity of VF progression to investigate the models' performances on predicting worsening cases. The models were additionally compared with a no-change model that uses the baseline VF (for the CNN) and the last-observed VF (for the RNN) for its prediction. Main Outcome Measures: PMAE in predictions. Results: The overall PMAE 95% confidence intervals were 2.21 to 2.24 decibels (dB) for the CNN and 2.56 to 2.61 dB for the RNN, which were close to the original studies' reported values. However, both models exhibited large errors in identifying patients with worsening VFs and often failed to outperform the no-change model. Pointwise mean absolute error values were higher in patients with greater changes in mean sensitivity (for the CNN) and mean total deviation (for the RNN) between baseline and follow-up VFs. Conclusions: Although our evaluation confirms the low overall PMAEs reported in the original studies, our findings also reveal that both models severely underpredict worsening of VF loss. Because the accurate detection and projection of glaucomatous VF decline is crucial in ophthalmic clinical practice, we recommend that this consideration is explicitly taken into account when developing and evaluating future deep learning models.

Acute Angle-Closure Attacks Are Uncommon in Primary Angle-Closure Suspects after Pharmacologic Mydriasis: The Zhongshan Angle-Closure Prevention Trial.

PURPOSE: Angle-closure glaucoma is a major cause of blindness worldwide that carries an excessive risk of severe, bilateral visual impairment. A common concern among clinicians is the precipitation of acute angle-closure (AAC) attacks because of mydriasis. We evaluated the risk of AAC after pharmacologic dilation in Chinese individuals classified as having bilateral primary angle-closure suspects (PACSs). DESIGN: Randomized, interventional, controlled trial. PARTICIPANTS: A total of 889 patients with bilateral PACSs, aged between 50 and 70 years, were identified through community screening in Guangzhou, China, and enrolled in the study. METHODS: In the Zhongshan Angle-Closure Prevention Trial, bilateral PACSs were treated with laser peripheral iridotomy (LPI) in 1 randomly selected eye, with the fellow eye serving as an untreated control. Over 72 months of follow-up, the participants had their pupils pharmacologically dilated 6 times with 5% phenylephrine and 0.5% tropicamide. MAIN OUTCOME MEASURES: Incidence and risk of post-mydriasis AAC in LPI-treated and untreated, control eyes classified as PACSs. RESULTS: One bilateral AAC attack occurred after mydriasis at the 2-week post-LPI visit. No other AAC events occurred in the LPI-treated eyes. In the untreated eyes, 4 additional attacks occurred: 2 occurred after dilation (1 at 54 months and 1 at 72 months of follow-up) and 2 occurred spontaneously. The risk of post-mydriasis AAC in the untreated eyes was 1 attack in 1587 dilations. The risk of spontaneous AAC in the untreated eyes was 0.44 per 1000 eye-years (95% confidence interval, 0.11-1.77 per 1000 eye-years). CONCLUSIONS: The risk of incident AAC attacks in PACSs was extremely low, even in a higher-risk group that underwent repeated pharmacologic pupillary dilation over 6 years of follow-up. Prophylactic LPI reduced this small but real risk. This trial was registered at ISRCTN.com as ISRCTN45213099.

Laser peripheral iridotomy for the prevention of angle closure: a single-centre, randomised controlled trial.

BACKGROUND: Primary angle-closure glaucoma affects 20 million people worldwide. People classified as primary angle closure suspects have a higher but poorly quantified risk of developing glaucoma. We aimed to assess efficacy and safety of laser peripheral iridotomy prophylaxis against primary angle-closure glaucoma in Chinese people classified as primary angle closure suspects. METHODS: In this randomised controlled trial, bilateral primary angle closure suspects aged 50-70 years were enrolled at the Zhongshan Ophthalmic Center, a tertiary specialised hospital in Guangzhou, China. Eligible patients received laser peripheral iridotomy in one randomly selected eye, with the other remaining untreated. The primary outcome was incident primary angle closure disease as a composite endpoint of elevation of intraocular pressure, peripheral anterior synechiae, or acute angle-closure during 72 months of follow-up in an intention-to-treat analysis between treated eyes and contralateral controls. This trial is registered with the ISRCTN registry, number ISRCTN45213099. FINDINGS: Of 11 991 screened individuals, 889 individuals were randomly assigned from June 19, 2008 (889 treated and 889 untreated eyes). Incidence of the primary outcome was 4·19 per 1000 eye-years in treated eyes compared with 7·97 per 1000 eye-years in untreated eyes (hazard ratio 0·53; 95% CI 0·30-0·92; p=0·024). A primary outcome event occurred in 19 treated eyes and 36 untreated eyes with a statistically significant difference using pair-wise analysis (p=0·0041). No serious adverse events were observed during follow-up. INTERPRETATION: Incidence of angle-closure disease was very low among individuals classified as primary angle closure suspects identified through community-based screening. Laser peripheral iridotomy had a modest, albeit significant, prophylactic effect. In view of the low incidence rate of outcomes that have no immediate threat to vision, the benefit of prophylactic laser peripheral iridotomy is limited; therefore, widespread prophylactic laser peripheral iridotomy for primary angle-closure suspects is not recommended. FUNDING: Fight for Sight, the Sun Yat-Sen University 5010 Project Fund, Moorfields Eye Charity, and the National Natural Science Foundation of China.

The Relationship Between Quantitative Pupillometry and Estimated Ganglion Cell Counts in Patients With Glaucoma.

PURPOSE: To assess the relationship between pupillary light reflex and estimated retinal ganglion cell (RGC) counts in patients with glaucoma. METHODS: We recorded and analyzed pupil responses using an automated binocular pupillometer in 148 patients with glaucoma (mean age 67±11, 49% female) and 71 controls (age 60±9.6, 69% female) as part of a prospective clinical study. The amplitude of pupil constriction was calculated as the percentage change in pupil diameter between constriction onset and peak constriction in response to controlled stimuli. The magnitude of a relative afferent pupillary defect (RAPD) was defined as the log of the ratio of the amplitude between 2 eyes multiplied by 10. RGC counts were estimated using empirical formulas that combine estimates from both functional (eccentricity and sensitivity measured by standard automated perimetry) and structural (retinal nerve fiber layer thickness) tests. For analyses performed at the level of individual eyes, we used multilevel modeling to account for between-eye correlations within individuals. RESULTS: Eyes with higher estimated RGC counts had a larger pupil response amplitude (z-score=8.24, P<0.001), shorter latency (z=-3.17, P=0.002), faster constriction velocity (z=6.64, P<0.001), shorter time to maximum constriction (z=-1.96, P=0.049), and longer time to maximum dilation (z=6.66, P<0.001). For every 0.3 log unit difference in RAPD score, there was an average decrease in estimated RGC count of 37,817 (P<0.001). CONCLUSIONS: There is a statistically significant association between estimated RGC count and pupillary response to stimuli. Quantitative pupillography may be useful in diagnosis and monitoring of optic neuropathies.

Effect of pH on optimization of photofermentative hydrogen production by co-culture of Rhodobacter sphaeroides-NMBL-02 and Bacillus firmus-NMBL-03.

Rhodobacter sphaeroides NMBL-02, photosynthetic purple non sulfur (PNS) bacteria and associated Bacillus firmus NMBL-03 were isolated from water sample collected from 15-20 inches beneath the surface of ponds from Northern region of India in modified Sistrom's media (120 ml) containing 3 g/L malate and 1.2 g/L ammonium sulfate. The isolation was done in air tight serum bottles (120 ml) under tungsten bulb (1.8 kLux light intensity) at 30 oC ± 2 oC. The PNS and heterotrophic bacteria associated with the culture was purified by clonal selection method and characterized by 16S rDNA sequencing. The PNS isolate was identified as Rhodobacter sphaeroides NMBL-02 (ID: 1467407, Accession BANKIT: JN256030) and associated heterotroph as Bacillus firmus NMBL-03 (Gene Bank Accession no.: JN 256029). The effect of initial medium pH on optimization of hydrogen production was investigated in batch process. The maximum hydrogen potential and hydrogen production rate was 2310 ± 55 ml/L and 4.75 ml/L culture/h respectively using glutamate (1.7 mmol/L) as nitrogen source and malate (22.38 mmol/L) as carbon source with 76.39% malate conversion efficiency at initial medium pH 5.0. This co-culture has the ability to produce significant amount of hydrogen in the pH range of 5.0 to 10.0 with 76.39% to 35.71% malate conversion respectively.

Results From a Modified Bleb Needling Procedure With Continuous Infusion Performed in the Operating Room.

PURPOSE: Needling of a scarred trabeculectomy bleb is often performed in the office using a slit-lamp microscope as an alternative to additional surgery to lower intraocular pressure (IOP). However, the success rate in an office setting is highly variable, with reported success rates as low as 13%. We report a retrospective assessment of an intraoperative needling technique for reviving failed blebs. DESIGN: A retrospective chart review. PARTICIPANTS: Patients undergoing the intraoperative modified bleb revision technique in the setting of a failed trabeculectomy due to scarring at the Wilmer Eye Institute, Johns Hopkins Hospital between August 16, 2010 and August 29, 2012. METHODS: Patients with uncontrolled IOP were operated on using a modified bleb needling technique. In this technique, a 25-G infusion cannula is placed in the anterior chamber and fibrotic adhesions within the bleb are lysed with a 25-G needle. The continuous infusion of balanced salt solution from the anterior chamber causes bleb elevation, which helps to guide the endpoint of lysis for the procedure. A subconjunctival injection of 5-fluorouracil is given at the conclusion of each case. MAIN OUTCOME MEASURES: IOP reduction and number of glaucoma medications at postoperative day 1, week 1, month 1, month 3, month 6, and month 12. RESULTS: A total of 33 eyes of 30 patients were included. At the visit before the procedure, the mean (±SD) IOP was 22.1±9.2 (range, 11 to 58) and subjects were using an average of 2.3±1.4 (range, 0 to 4) glaucoma medications. The mean IOP reduction was 8.7 mm Hg [95% confidence interval (CI), 5.6-11.8] at postoperative day 1, 8.1 mm Hg (95% CI, 4.0-12.3) at week 1, 8.9 mm Hg (95% CI, 5.3-12.5) at month 1, 8.1 mm Hg (95% CI, 4.2-12.0) at month 3, 8.2 mm Hg (95% CI, 3.9-12.5) at month 6, and 6.2 mm Hg (95% CI, 3.6-8.7) at month 12. IOP was reduced about 30% to 40% compared with baseline at each time point (P<0.05). The average reduction in medications used was 1.7 at day 1, 1.0 at month 1, 1.2 at month 3, 1.5 at month 6, and 0.5 at month 12. Seven patients underwent repeat needling. Overall, 64% of subjects maintained IOP at or below their target after 12 months. CONCLUSIONS: A modified bleb needling procedure performed in the operating room can successfully lower IOP in the setting of a previous trabeculectomy in over 60% of subjects a year after the procedure.

Electronic monitoring to assess adherence with once-daily glaucoma medications and risk factors for nonadherence: the automated dosing reminder study.

IMPORTANCE: Adherence with topical glaucoma medications is low in some patients. To identify these patients, we need more information on risk factors for nonadherence. OBJECTIVE: To assess adherence with once-daily glaucoma medication. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study involving patients who were recruited from a university-based glaucoma clinic and treated with once-daily prostaglandin eyedrops. Baseline characteristics were recorded, and each patient was provided a medication bottle to hold his or her eyedrop bottle throughout the study. An electronic cap recorded each time the larger bottle holding the eyedrops was opened. Participants were administered standardized tests of depression and mental status and answered questions about their health and their attitudes toward medication adherence. They used the electronic monitors for 3 months, during which their adherence with medications was assessed. MAIN OUTCOMES AND MEASURES: Adherence with daily glaucoma medication and factors associated with poor adherence. RESULTS: Of the 491 participants enrolled, 407 (82.9%) successfully completed the 3-month adherence assessment. Of this group, 337 (82.8%) took their medication correctly on at least 75% of days and were deemed adherent. Compared with this adherent group, the 70 participants (17.2%) who were nonadherent were slightly younger, were more likely to be of African descent, took medications for a shorter time, had a lower level of educational attainment, and had worse scores on mental status and depression scales (P < .05 for all). Nonadherent participants were less likely to be able to name their glaucoma medications, reported a lower estimate of adherence, and were more likely to admit some missed doses over the past 2 weeks or in general (P < .05 for all). Those who were nonadherent were also less likely to agree that remembering their eyedrops is easy, more likely to strongly agree with the statement that eyedrops can cause problems, and less likely to agree that they followed physicians' orders. CONCLUSIONS AND RELEVANCE: Electronic monitoring of patient adherence documented that a sizable number of patients with glaucoma do not take their medications as prescribed. Factors were identified that may prove useful in targeting those nonadherent patients for interventions.

Automated telecommunication-based reminders and adherence with once-daily glaucoma medication dosing: the automated dosing reminder study.

IMPORTANCE: Topical glaucoma medications lower intraocular pressure and alter the course of the disease. Because adherence with glaucoma medications is a known problem, interventions are needed to help those patients who do not take their medications as prescribed. OBJECTIVE: To assess the ability of an automated telecommunication-based intervention to improve adherence with glaucoma medications. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective cohort study of medication adherence, followed by a randomized intervention for those found to be nonadherent, of individuals recruited from a university-based glaucoma subspecialty clinic. A total of 491 participants were enrolled in the initial assessment of adherence. Of those, 70 were nonadherent with their medications after 3 months of electronic monitoring and randomized to intervention and control groups. INTERVENTIONS: A personal health record was used to store the list of patient medications and reminder preferences. On the basis of those data, participants randomized to the intervention received daily messages, either text or voice, reminding them to take their medication. Participants randomized to the control group received usual care. MAIN OUTCOMES AND MEASURES: Difference in adherence before and after initiation of the intervention. RESULTS: Using an intent-to-treat analysis, we found that the median adherence rate in the 38 participants randomized to the intervention increased from 53% to 64% (P < .05). There was no statistical change in 32 participants in the control group. To assess the real efficacy of the intervention, the same comparison was performed for the participants who successfully completed the study after randomization. Analyzed this way, the adherence rate in the 20 participants in the intervention group increased from 54% to 73% (P < .05), whereas there was again no statistical change in the 19 participants in the control group. Eighty-four percent of the participants who received reminders agreed they were helpful and would continue using them outside the study. CONCLUSIONS AND RELEVANCE: Automated telecommunication-based reminders linked to data in a personal health record improved adherence with once-daily glaucoma medications. This is an effective method to improve adherence that could realistically be implemented in ophthalmology practices with a minimum amount of effort on the part of the practice or the patient.

Longitudinal changes of angle configuration in primary angle-closure suspects: the Zhongshan Angle-Closure Prevention Trial.

OBJECTIVE: To determine longitudinal changes in angle configuration in the eyes of primary angle-closure suspects (PACS) treated by laser peripheral iridotomy (LPI) and in untreated fellow eyes. DESIGN: Longitudinal cohort study. PARTICIPANTS: Primary angle-closure suspects aged 50 to 70 years were enrolled in a randomized, controlled clinical trial. METHODS: Each participant was treated by LPI in 1 randomly selected eye, with the fellow eye serving as a control. Angle width was assessed in a masked fashion using gonioscopy and anterior segment optical coherence tomography (AS-OCT) before and at 2 weeks, 6 months, and 18 months after LPI. MAIN OUTCOME MEASURES: Angle width in degrees was calculated from Shaffer grades assessed under static gonioscopy. Angle configuration was also evaluated using angle opening distance (AOD250, AOD500, AOD750), trabecular-iris space area (TISA500, TISA750), and angle recess area (ARA) measured in AS-OCT images. RESULTS: No significant difference was found in baseline measures of angle configuration between treated and untreated eyes. At 2 weeks after LPI, the drainage angle on gonioscopy widened from a mean of 13.5° at baseline to a mean of 25.7° in treated eyes, which was also confirmed by significant increases in all AS-OCT angle width measures (P<0.001 for all variables). Between 2 weeks and 18 months after LPI, a significant decrease in angle width was observed over time in treated eyes (P<0.001 for all variables), although the change over the first 5.5 months was not statistically significant for angle width measured under gonioscopy (P = 0.18), AOD250 (P = 0.167) and ARA (P = 0.83). In untreated eyes, angle width consistently decreased across all follow-up visits after LPI, with a more rapid longitudinal decrease compared with treated eyes (P values for all variables ≤0.003). The annual rate of change in angle width was equivalent to 1.2°/year (95% confidence interval [CI], 0.8-1.6) in treated eyes and 1.6°/year (95% CI, 1.3-2.0) in untreated eyes (P<0.001). CONCLUSIONS: Angle width of treated eyes increased markedly after LPI, remained stable for 6 months, and then decreased significantly by 18 months after LPI. Untreated eyes experienced a more consistent and rapid decrease in angle width over the same time period.

Assessment of a rapid method to determine approximate visual acuity in large surveys and other such settings.

PURPOSE: To evaluate the efficacy of an iPod application developed to rapidly measure approximate visual acuity (VA). DESIGN: Prospective, cross-sectional study. METHODS: One hundred four subjects (104 eyes) with a wide range of VA underwent both Early Treatment Diabetic Retinopathy Study (ETDRS) VA testing and iPod application testing. The application presented 4 randomized ETDRS letters at the Snellen equivalent of 20/40 and 20/200 each. In separate analyses, sensitivity and specificity of the iPod test were determined using the ETDRS VA testing results as the gold standard and defining "failure" to see as identifying 1, 2, 3, or all 4 letters incorrectly out of 4 trials. The minimum number of iPod trials necessary to maintain high accuracy was determined by defining a "failure" as getting the first, first 2, first 3, or all trial letters incorrect. In 13 subjects, the time necessary to perform the testing was determined. RESULTS: Forty-six subjects had an ETDRS Snellen equivalent VA ≥20/40; 45 had a VA <20/40 and ≥20/200; and 13 had a VA <20/200. The mean ± SD testing time for the 3 groups was 43 ± 13, 60 ± 15, and 72 ± 25 seconds, respectively. The highest sensitivity and specificity combination was observed when a "failure" was defined as getting all letters incorrect for both the 20/40 (sensitivity = 98.3%/specificity = 93.5%) and 20/200 (sensitivity/specificity both 92.3%) cutoffs. CONCLUSIONS: An iPod application requiring about a 1-minute testing time provides an objective, portable, rapid, and low-cost method to determine approximate VA, allowing VA testing to be performed efficiently in large surveys and other settings where approximate VA should be measured.

Development and validation of an associative model for the detection of glaucoma using pupillography.

PURPOSE: To develop and validate an associative model using pupillography that best discriminates those with and without glaucoma. DESIGN: A prospective case-control study. METHODS: We enrolled 148 patients with glaucoma (mean age 67 ± 11) and 71 controls (mean age 60 ± 10) in a clinical setting. This prototype pupillometer is designed to record and analyze pupillary responses at multiple, controlled stimulus intensities while using varied stimulus patterns and colors. We evaluated three approaches: (1) comparing the responses between the two eyes; (2) comparing responses to stimuli between the superonasal and inferonasal fields within each eye; and (3) calculating the absolute pupil response of each individual eye. Associative models were developed using stepwise regression or forward selection with Akaike information criterion and validated by fivefold cross-validation. We assessed the associative model using sensitivity, specificity and the area-under-the-receiver operating characteristic curve. RESULTS: Persons with glaucoma had more asymmetric pupil responses in the two eyes (P < 0.001); between superonasal and inferonasal visual field within the same eye (P = 0.014); and smaller amplitudes, slower velocities and longer latencies of pupil responses compared to controls (all P < 0.001). A model including age and these three components resulted in an area-under-the-receiver operating characteristic curve of 0.87 (95% CI 0.83 to 0.92) with 80% sensitivity and specificity in detecting glaucoma. This result remained robust after cross-validation. CONCLUSIONS: Using pupillography, we were able to discriminate among persons with glaucoma and those with normal eye examinations. With refinement, pupil testing may provide a simple approach for glaucoma screening.

Accuracy of pupil assessment for the detection of glaucoma: a systematic review and meta-analysis.

OBJECTIVE: To assess the accuracy of using pupillary light reflex (PLR) in detecting glaucoma. CLINICAL RELEVANCE: Glaucoma is a specific disease of the optic nerve and is often more severe in 1 eye. When large enough, this asymmetry in disease severity can cause a relative afferent pupillary defect (RAPD). Better detection of RAPDs may be one way to identify persons with glaucoma. METHODS: We searched Medline and Embase through June 2012 and searched bibliographies for relevant studies for additional references. Two authors independently reviewed all articles and selected studies that assessed PLRs in patients with glaucoma. We analyzed data using mixed-effect bivariate summary receiver operating characteristic meta-analysis models. RESULTS: A total of 30 studies were included in this review. An RAPD was observed in 9% to 82% of patients with glaucoma. Eleven studies with a total of 7271 participants were included in the analysis, and the pooled estimate corresponded to a sensitivity of 0.63 (95% confidence interval [CI], 0.43-0.80) and a specificity of 0.93 (95% CI, 0.85-0.97). After excluding 2 studies that used the swinging flashlight test, the sensitivity increased to 0.74 (95% CI, 0.59-0.85) with a specificity of 0.85 (95% CI, 0.77-0.90). Study designs and different pupil measurement techniques explained part of the heterogeneity between studies. CONCLUSIONS: Patients with glaucoma frequently have an abnormal PLR and comparing the responses between the 2 eyes can in part distinguish between those with glaucoma and those without the disease. Newer instruments and analytic approaches to assess pupil function may improve the performance of pupil screening.

Symmetry of the pupillary light reflex and its relationship to retinal nerve fiber layer thickness and visual field defect.

PURPOSE: To assess the relationship between the pupillary light reflex (PLR) and visual field (VF) mean deviation (MD) and retinal nerve fiber layer (RNFL) thickness. METHODS: A total of 148 patients with glaucoma (mean age 67 ± 11, 49% female) and 71 controls (mean age 60 ± 10, 69% female) were included in this study. Using a pupillometer, we recorded and analyzed pupillary responses at varied stimulus patterns (full field, superonasal and inferonasal quadrant arcs). We compared the responses between the two eyes, compared responses to stimuli in the superonasal and inferonasal fields within each eye, and calculated the absolute PLR value of each individual eye. We assessed the relationship among PLR, MD, and RNFL thickness using the Pearson correlation coefficient. For analyses performed at the level of individual eyes, we used multilevel modeling to account for between-eye correlations within individuals. RESULTS: For every 0.3 log unit difference in between-eye asymmetry of PLR, there was an average 2.6-dB difference in visual field MD (correlation coefficient R = 0.83, P < 0.001) and a 3.2-µm difference in RNFL thickness between the two eyes (R = 0.67, P < 0.001). Greater VF damage and thinner RNFL for each individual eye were associated with smaller response amplitude, slower velocity, and longer time to peak constriction and dilation after adjusting for age and sex (all P < 0.001). However, within-eye asymmetry of PLR between superonasal and inferonasal stimulation was not associated with corresponding within-eye differences in VF or RNFL. CONCLUSIONS: As measured by this particular device, the PLR is strongly correlated with VF functional testing and measurements of RNFL thickness.

Development and validation of a predictive model for nonadherence with once-daily glaucoma medications.

OBJECTIVE: To develop and validate a predictive model to estimate the probability of being nonadherent to topical glaucoma medications. DESIGN: Prospective cohort study. PARTICIPANTS: Patients being treated with once-daily prostaglandin eye drops. METHODS: A predictive model for nonadherence was developed from the Travatan Dosing Aid (TDA) study (n = 196) using stepwise logistic regression. The performance of the TDA-derived model was assessed using a separate cohort of subjects from the Automated Dosing Reminder Study (ADRS; n = 407). The assessment was based on regression coefficients, discrimination, and calibration. We also developed a scoring system from the TDA-derived model to simplify the estimation of risk for clinical use. MAIN OUTCOME MEASURES: Usage of drops was monitored electronically for 3 months in both studies. Adherence was calculated as the percentage of days on which a dose was taken within 4 hours of the average dosing time for that patient. Nonadherence was defined as taking ≤ 75% prescribed doses within a window starting 2 weeks after the baseline visit until 2 weeks before the follow-up visit. RESULTS: Six factors, including younger age, black race, worse general health status, shorter duration of glaucoma medication therapy, lower self-reported adherence, and admitting to not following doctors' orders, were associated with being nonadherent and were included in the predictive model. The coefficients for the TDA-derived and the ADRS-derived predictive models were similar. The risk scoring system developed from the TDA study had good discrimination (area under the receiver operating characteristic curve of 0.80) and calibration (Hosmer-Lemeshow goodness-of-fit test, P = 0.102) when applied to the ADRS population. CONCLUSIONS: The TDA-derived predictive model for nonadherence performed well in an independent population. A risk scoring system was developed using demographic data and patient responses to 4 questions to provide an estimate of the probability of being nonadherent.