Are Patient Self-Reported Outcome Measures Sensitive Enough to Be Used as End Points in Clinical Trials? Evidence from the United Kingdom Glaucoma Treatment Study

PURPOSE: The United Kingdom Glaucoma Treatment Study (UKGTS) demonstrated the effectiveness of an intraocular pressure-lowering drug in patients with glaucoma using visual field progression as a primary outcome. The present study tested the hypothesis that responses on patient-reported outcome measures (PROMs; secondary outcome measure) differ between patients receiving a topical prostaglandin analog (latanoprost) or placebo eye drops in UKGTS. DESIGN: Multicenter, randomized, triple-masked, placebo-controlled trial. PARTICIPANTS: Newly diagnosed glaucoma patients in the UKGTS with baseline and exit PROMs (n = 182 and n = 168 patients from the treatment and placebo groups, respectively). METHODS: In the UKGTS (trial registration number, ISRCTN96423140), patients with open-angle glaucoma were allocated to receive latanoprost (treatment) or placebo; the observation period was 24 months. Patients completed general health PROMs (European Quality of Life in 5 Dimensions [EQ-5D] and 36-item Short Form [SF-36]) and PROMs specific to glaucoma (15-item Glaucoma Quality of Life [GQL-15] and 9-item Glaucoma Activity Limitation [GAL-9]) at baseline and exit from the trial. Percentage changes between measurement on PROMs were calculated for each patient and compared between treatment arms. In addition, differences between stable patients (n = 272) and those with glaucomatous progression (n = 78), as determined by visual field change (primary outcome), were assessed. MAIN OUTCOME MEASURE: PROMs on health-related and vision-related quality of life. RESULTS: Average percentage change on PROMs was similar for patients in both arms of the trial, with no statistically significant differences between treatment and placebo groups (EQ-5D, P = 0.98; EQ-5D visual analog scale, P = 0.88; SF-36, P = 0.94, GQL-15, P = 0.66; GAL-9, P = 0.87). There were statistically significant differences between stable and progressing patients on glaucoma-specific PROMs (GQL-15, P = 0.02; GAL-9, P = 0.02), but not on general health PROMs (EQ-5D, P = 0.62; EQ-5D visual analog scale, P = 0.23; SF-36, P = 0.65). CONCLUSIONS: Average change in PROMs on health-related and vision-related quality of life was similar for the treatment and placebo groups in the UKGTS. The PROMs used may not be sensitive enough to function as primary end points in clinical trials when participants have newly diagnosed early-stage glaucoma

Improving the Accuracy and Speed of Visual Field Testing in Glaucoma With Structural Information and Deep Learning

Purpose: To assess the performance of a perimetric strategy using structure–function predictions from a deep learning (DL) model. Methods: Visual field test–retest data from 146 eyes (75 patients) with glaucoma with (median [5th–95th percentile]) 10 [7, 10] tests per eye were used. Structure–function predictions were generated with a previously described DL model using cicumpapillary optical coherence tomography (OCT) scans. Structurally informed prior distributions were built grouping the observed measured sensitivities for each predicted value and recalculated for each subject with a leave-one-out approach. A zippy estimation by sequential testing (ZEST) strategy was used for the simulations (1000 per eye). Groundtruth sensitivities for each eye were the medians of the test–retest values. Two variations of ZEST were compared in terms of speed (average total number of presentations [NP] per eye) and accuracy (average mean absolute error [MAE] per eye), using either a combination of normal and abnormal thresholds (ZEST) or the calculated structural distributions (S-ZEST) as prior information. Two additional versions of these strategies employing spatial correlations were tested. Results: S-ZEST was significantly faster, with a mean average NP of 213.87 (SD = 28.18), than ZEST, with a mean average NP of 255.65 (SD = 50.27) (P < 0.001). The average MAE was smaller for S-ZEST (1.98; SD = 2.37) than ZEST (2.43; SD = 2.69) (P < 0.001). Spatial correlations further improved both strategies (P < 0.001), but the differences between ZEST and S-ZEST remained significant (P < 0.001). Conclusions: DL structure–function predictions can significantly improve perimetric tests. Translational Relevance: DL structure–function predictions from clinically available OCT scans can improve perimetry in glaucoma patients

Spatiotemporal summation of perimetric stimuli in healthy observers

Spatial summation of perimetric stimuli has been used to derive conclusions about the spatial extent of retinal-cortical convergence, mostly from the size of the critical area of summation (Ricco's area, RA) and critical number of retinal ganglion cells (RGCs). However, spatial summation is known to change dynamically with stimulus duration. Conversely, temporal summation and critical duration also vary with stimulus size. Such an important and often neglected spatiotemporal interaction has important implications for modeling perimetric sensitivity in healthy observers and for formulating hypotheses for changes measured in disease. In this work, we performed experiments on visually heathy observers confirming the interaction of stimulus size and duration in determining summation responses in photopic conditions. We then propose a simplified computational model that captures these aspects of perimetric sensitivity by modelling the total retinal input, the combined effect of stimulus size, duration, and retinal cones-to-RGC ratio. We additionally show that, in the macula, the enlargement of RA with eccentricity might not correspond to a constant critical number of RGCs, as often reported, but to a constant critical total retinal input. We finally compare our results with previous literature and show possible implications for modeling disease, especially glaucoma

Revisiting the Drasdo Model: Implications for Structure-Function Analysis of the Macular Region

Purpose: To provide a consistent implementation of a retinal ganglion cell (RGC) displacement model proposed by Drasdo et al. for macular structure-function analysis, customizable by axial length (AL). Methods: The effect of axial length on the shape of the inner retina was measured on 235 optical coherence tomography (OCT) scans from healthy eyes, to provide evidence for geometric scaling of structures with eye size. Following this assumption, we applied the Drasdo model to map perimetric stimuli on the radially displaced RGCs using two different methods: Method 1 only displaced the center of the stimuli; Method 2 applied the displacement to every point on the edge of the stimuli. We compared the accuracy of the two methods by calculating, for each stimulus, the number of expected RGC receptive fields and the number RGCs calculated from the histology map, expected to be equivalent. The same calculation was repeated on RGC density maps derived from 28 OCT scans from 28 young healthy subjects (age < 40 years) to confirm our results on clinically available measurements. Results: The size of the retinal structures significantly increased with AL (P < 0.001) and was well predicted by geometric scaling. Method 1 systematically underestimated the RGC counts by as much as 60%. No bias was observed with Method 2. Conclusions: The Drasdo model can effectively account for AL assuming geometric scaling. Method 2 should be used for structure-function analyses. Translational Relevance: We developed a free web App in Shiny R to make our results available for researchers

Elevated Intraocular Pressure After Intravitreal Steroid Injection in Diabetic Macular Edema: Monitoring and Management

INTRODUCTION: With the increasing use of intravitreal administration of corticosteroids in macular edema, steroid-induced intraocular pressure (IOP) rise is becoming an emergent issue. However, for patients in whom intravitreal steroids are indicated, there are no specific recommendations for IOP monitoring and management after intravitreal administration of corticosteroids. METHOD: An expert panel of European ophthalmologists reviewed evidence on corticosteroid-induced IOP elevation. The objective of the panel was to propose an algorithm based on available literature and their own experience for the monitoring and management of corticosteroid-induced IOP elevation, with a focus on diabetic patients. RESULTS: Data from trials including diabetic patients with a rise of IOP after intravitreal steroid administration indicate that IOP-lowering medical treatment is sufficient for a large majority of patients; only a small percentage underwent laser trabeculoplasty or filtering filtration surgery. A 2-step algorithm is proposed that is based on the basal value of IOP and evidence for glaucoma. The first step is a risk stratification before treatment. Patients normotensive at baseline (IOP ≤ 21 mmHg), do not require additional baseline diagnostic tests. However, patients with baseline ocular hypertension (OHT) (IOP > 21 mmHg) should undergo baseline imaging and visual field testing. The second step describes monitoring and treatment after steroid administration. During follow-up, patients developing OHT should have baseline and periodical imaging and visual field testing; IOP-lowering treatment is proposed only if IOP is >25 mmHg or if diagnostic tests suggest developing glaucoma. CONCLUSION: The management and follow-up of OHT following intravitreal corticosteroid injection is similar to that of primary OHT. If OHT develops, IOP is controlled in a large proportion of patients with standard IOP treatments. The present algorithm was developed to assist ophthalmologists with guiding principles in the management of corticosteroid-induced IOP elevation. FUNDING: Alimera Sciences Limited

Comparison of neuroretinal rim area measurements made by the Heidelberg Retina Tomograph I and the Heidelberg Retina Tomograph II

To investigate the agreement between neuroretinal rim area (RA) measurements using the Heidelberg Retina Tomograph I (HRT Classic) and Heidelberg Retina Tomograph II (HRT II). To compare apparent RA changes in follow-up series of HRT II topographies when using either an HRT Classic or HRT II mean topography as baseline

Neural Network-Based Retinal Nerve Fiber Layer Profile Compensation for Glaucoma Diagnosis in Myopia: Model Development and Validation

BACKGROUND: Due to the axial elongation-associated changes in the optic nerve and retina in high myopia, traditional methods like optic disc evaluation and visual field are not able to correctly differentiate glaucomatous lesions. It has been clinically challenging to detect glaucoma in highly myopic eyes. OBJECTIVE: This study aimed to develop a neural network to adjust for the dependence of the peripapillary retinal nerve fiber layer (RNFL) thickness (RNFLT) profile on age, gender, and ocular biometric parameters and to evaluate the network's performance for glaucoma diagnosis, especially in high myopia. METHODS: RNFLT with 768 points on the circumferential 3.4-mm scan was measured using spectral-domain optical coherence tomography. A fully connected network and a radial basis function network were trained for vertical (scaling) and horizontal (shift) transformation of the RNFLT profile with adjustment for age, axial length (AL), disc-fovea angle, and distance in a test group of 2223 nonglaucomatous eyes. The performance of RNFLT compensation was evaluated in an independent group of 254 glaucoma patients and 254 nonglaucomatous participants. RESULTS: By applying the RNFL compensation algorithm, the area under the receiver operating characteristic curve for detecting glaucoma increased from 0.70 to 0.84, from 0.75 to 0.89, from 0.77 to 0.89, and from 0.78 to 0.87 for eyes in the highest 10% percentile subgroup of the AL distribution (mean 26.0, SD 0.9 mm), highest 20% percentile subgroup of the AL distribution (mean 25.3, SD 1.0 mm), highest 30% percentile subgroup of the AL distribution (mean 24.9, SD 1.0 mm), and any AL (mean 23.5, SD 1.2 mm), respectively, in comparison with unadjusted RNFLT. The difference between uncompensated and compensated RNFLT values increased with longer axial length, with enlargement of 19.8%, 18.9%, 16.2%, and 11.3% in the highest 10% percentile subgroup, highest 20% percentile subgroup, highest 30% percentile subgroup, and all eyes, respectively. CONCLUSIONS: In a population-based study sample, an algorithm-based adjustment for age, gender, and ocular biometric parameters improved the diagnostic precision of the RNFLT profile for glaucoma detection particularly in myopic and highly myopic eyes

Risk factors for visual field deterioration in the United Kingdom Glaucoma Treatment Study

OBJECTIVE: The United Kingdom Glaucoma Treatment Study (UKGTS) investigated the visual field (VF) preserving effect of medical treatment in open-angle glaucoma (OAG). The objective of this analysis was to identify risk factors associated with VF deterioration. DESIGN: Randomized, double masked, placebo-controlled, multicentre trial. PARTICIPANTS: Five hundred sixteen participants with previously untreated OAG were prospectively recruited in 10 UK centres. METHODS: Eligibility criteria were modeled on those for the Early Manifest Glaucoma Trial. Study participants were randomized to either latanoprost 0.005% or placebo eye drops. The observation period was 2 years and involved, among other procedures, VF testing and intraocular pressure (IOP) measurement at 11 scheduled visits, with clustering of tests at baseline, 18 months, and 24 months. Guided Progression Analysis pattern deviation maps were used to determine VF deterioration. Cox regression was used to compute the hazard ratios (HRs) and respective 95% confidence intervals (CIs) whilst accounting for the correlation within sites. Model selection was guided by backwards stepwise selection conducted on the model containing all variables which were significant at the 0.2 level in the univariable analysis. Follow-up variables which showed collinearity with baseline values were not retained in the final model. MAIN OUTCOME MEASURES: Time-to-VF deterioration. RESULTS: Treatment with latanoprost reduced the HR for VF deterioration by 58% (HR 0.42; 95% CI 0.27-0.67, P=0.001). Factors associated with deterioration were bilateral disease (HR 1.59 for yes versus no; 95% CI 1.02-2.50, P=0.041), higher baseline IOP (HR 1.07 per mmHg; 95% CI 1.02-1.12, P=0.008) and disc haemorrhage at visit 1 (HR 2.08; 95% CI 1.07-4.04, P=0.030). Smoking (current or previous) was associated with a reduced HR for VF deterioration (HR 0.59; 95% CI 0.37-0.93, P=0.023). No other evaluated factors were found to be statistically significant in the multivariable analysis. CONCLUSIONS: In the UKGTS, treatment with latanoprost halved VF deterioration risk. Bilateral disease, higher IOP and disc haemorrhage were confirmed as risk factors for deterioration; smoking history appeared to be protective against VF deterioration