Catherine Egan

A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT Study): 12-Month Data: Report 2

PURPOSE To report the findings at 1 year of a study comparing repeated intravitreal bevacizumab (ivB) and modified Early Treatment of Diabetic Retinopathy Study (ETDRS) macular laser therapy (MLT) in patients with persistent clinically significant diabetic macular edema (CSME). DESIGN Prospective, randomized, masked, single-center, 2-year, 2-arm clinical trial. PARTICIPANTS A total of 80 eyes of 80 patients with center-involving CSME and at least 1 prior MLT. METHODS Subjects were randomized to either ivB (6 weekly; minimum of 3 injections and maximum of 9 injections in the first 12 months) or MLT (4 monthly; minimum of 1 treatment and maximum of 4 treatments in the first 12 months). MAIN OUTCOME MEASURES The primary end point was the difference in ETDRS best-corrected visual acuity (BCVA) at 12 months between the bevacizumab and laser arms. RESULTS The baseline mean ETDRS BCVA was 55.7+/-9.7 (range 34-69) in the bevacizumab group and 54.6+/-8.6 (range 36-68) in the laser arm. The mean ETDRS BCVA at 12 months was 61.3+/-10.4 (range 34-79) in the bevacizumab group and 50.0+/-16.6 (range 8-76) in the laser arm (P = 0.0006). Furthermore, the bevacizumab group gained a median of 8 ETDRS letters, whereas the laser group lost a median of 0.5 ETDRS letters (P = 0.0002). The odds of gaining > or =10 ETDRS letters over 12 months were 5.1 times greater in the bevacizumab group than in the laser group (adjusted odds ratio, 5.1; 95% confidence interval, 1.3-19.7; P = 0.019). At 12 months, central macular thickness decreased from 507+/-145 microm (range 281-900 microm) at baseline to 378+/-134 microm (range 167-699 microm) (P<0.001) in the ivB group, whereas it decreased to a lesser extent in the laser group, from 481+/-121 microm (range 279-844 microm) to 413+/-135 microm (range 170-708 microm) (P = 0.02). The median number of injections was 9 (interquartile range [IQR] 8-9) in the ivB group, and the median number of laser treatments was 3 (IQR 2-4) in the MLT group. CONCLUSIONS The study provides evidence to support the use of bevacizumab in patients with center-involving CSME without advanced macular ischemia.

Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study.

Objectives To evaluate the efficacy and safety of intravitreous bevacizumab injections for the treatment of neovascular age related macular degeneration. Design Prospective, double masked, multicentre, randomised controlled trial. Setting Three ophthalmology centres in the United Kingdom. Participants 131 patients (mean age 81) with wet age related macular degeneration randomised 1:1 to intervention or control. Interventions Intravitreous bevacizumab (1.25 mg, three loading injections at six week intervals followed by further treatment if required at six week intervals) or standard treatment available at the start of the trial (photodynamic treatment with verteporfin for predominantly classic type neovascular age related macular degeneration, or intravitreal pegaptanib or sham treatment for occult or minimally classic type neovascular age related macular degeneration). Main outcome measures Primary outcome: proportion of patients gaining ≥15 letters of visual acuity at one year (54 weeks). Secondary outcomes: proportion of patients with stable vision and mean change in visual acuity. Results Of the 131 patients enrolled in the trial, five patients did not complete the study because of adverse events, loss to follow-up, or death. In the bevacizumab group, 21 (32%) patients gained 15 or more letters from baseline visual acuity compared with two (3%) in the standard care group (P<0.001); the estimated adjusted odds ratio was 18.1 (95% confidence interval 3.6 to 91.2) and the number needed to treat was 4 (3 to 6). In addition, the proportion of patients who lost fewer than 15 letters of visual acuity from baseline was significantly greater among those receiving bevacizumab treatment (91% (59) v 67% (44) in standard care group; P<0.001). Mean visual acuity increased by 7.0 letters in the bevacizumab group with a median of seven injections compared with a decrease of 9.4 letters in the standard care group (P<0.001), and the initial improvement at week 18 (plus 6.6 letters) was sustained to week 54. Among 65 patients treated with bevacizumab, there were no cases of endophthalmitis or serious uveitis related to the intervention. All end points with respect to visual acuity in the study eye at 54 weeks favoured bevacizumab treatment over standard care. Conclusions Bevacizumab 1.25 mg intavitreous injections given as part of a six weekly variable retreatment regimen is superior to standard care (pegaptanib sodium, verteporfin, sham), with low rates of serious ocular adverse events. Treatment improved visual acuity on average at 54 weeks. Trial registration number Current controlled trials ISRCTN83325075

Test-Retest Variability of Microperimetry Using the Nidek MP1 in Patients with Macular Disease

PURPOSE To determine the test-retest variability of the retinal sensitivity of the Nidek MP1 microperimeter in patients with macular disease. METHODS In this prospective study, 50 patients were enrolled with a range of macular diseases. One examiner performed two consecutive microperimetry tests for all patients using the same test strategy. Test-retest variability for mean sensitivity (MS), mean deviation (MD), point-wise sensitivity (PWS), local defect classification (LDC), average sensitivity for the central macula (CMS, 16 loci inside 10 degrees ), paracentral macular sensitivity (PMS, 52 loci in the 10 to 20 degrees ring), and dense scotoma size (DSS) were analyzed by calculating the 95% coefficients of repeatability or percentage agreement. RESULTS Mean (SD) age and visual acuity were 61 (15) years and 0.34 (0.32) logMAR, respectively. The mean difference in MS between tests 1 and 2 was +0.2 dB (SD, 0.9 dB; P = 0.127). The coefficients of repeatability for MS, MD, CMS, and PMS were 1.81, 2.56, 2.13, and 1.93 dB, respectively. The mean (SD) of coefficients of repeatability for PWS across all 68 loci was 5.56 (0.86) dB. Of all test loci in all patients 76% had perfect agreement in LDC, and 94% of patients had a change in DSS of four or fewer test loci. CONCLUSIONS Test-retest variability was lowest for MS and highest for PWS. However, MS does not provide spatial information. The authors recommend the use of CMS and PMS for monitoring macular function and consider a change of greater than 2.56 and 2.31 dB (the upper limit of the 95% confidence interval of their coefficients of repeatability), respectively, to exceed test-retest variability.

Patterns of peripheral retinal and central macula ischemia in diabetic retinopathy as evaluated by ultra-widefield fluorescein angiography

PURPOSE To investigate the association between peripheral and central ischemia in diabetic retinopathy. DESIGN Retrospective, cross-sectional. METHODS Consecutive ultra-widefield fluorescein angiography images were collected from patients with diabetes over a 12-month period. Parameters quantified include the foveal avascular zone (FAZ) area, peripheral ischemic index, peripheral leakage index, and central retinal thickness measurements, as well as visual acuity. The peripheral ischemia or leakage index was calculated as the area of capillary nonperfusion or leakage, expressed as a percentage of the total retinal area. RESULTS Forty-seven eyes of 47 patients were included. A moderate correlation was observed between the peripheral ischemia index and FAZ area (r = 0.49, P = .0001). A moderate correlation was also observed between the peripheral leakage index and FAZ area, but only in eyes that were laser naïve (r = 0.44, P = .02). A thinner retina was observed in eyes with macular ischemia (217 ± 81.8 μm vs 272 ± 36.0 μm) (P = .02), but not peripheral ischemia (258 ± 76.3 μm vs 276 ± 68.0 μm) (P = .24). The relationships between different patterns of peripheral and central macular pathology and visual acuity were evaluated in a step-wise multivariable regression model, and the variables that remained independently associated were age (r = 0.33, P = .03), FAZ area (r = 0.45, P = .02), and central retinal thickness (r = 0.38, P = .01), (R(2)-adjusted = 0.36). CONCLUSIONS Ultra-widefield fluorescein angiography provides an insight into the relationships between diabetic vascular complications in the retinal periphery and central macula. Although we observed relationships between ischemia and vascular leakage in the macula and periphery, it was only macular ischemia and retinal thinning that was independently associated with a reduced visual function.

Clinical and Molecular Analysis of Stargardt Disease With Preserved Foveal Structure and Function

PURPOSE To describe a cohort of patients with Stargardt disease who show a foveal-sparing phenotype. DESIGN Retrospective case series. METHODS The foveal-sparing phenotype was defined as foveal preservation on autofluorescence imaging, despite a retinopathy otherwise consistent with Stargardt disease. Forty such individuals were ascertained and a full ophthalmic examination was undertaken. Following mutation screening of ABCA4, the molecular findings were compared with those of patients with Stargardt disease but no foveal sparing. RESULTS The median age of onset and age at examination of 40 patients with the foveal-sparing phenotype were 43.5 and 46.5 years. The median logMAR visual acuity was 0.18. Twenty-two patients (22/40, 55%) had patchy parafoveal atrophy and flecks; 8 (20%) had numerous flecks at the posterior pole without atrophy; 7 (17.5%) had mottled retinal pigment epithelial changes; 2 (5%) had multiple atrophic lesions, extending beyond the arcades; and 1 (2.5%) had a bulls-eye appearance. The median central foveal thickness assessed with spectral-domain optical coherence tomographic images was 183.0 μm (n = 33), with outer retinal tubulation observed in 15 (45%). Twenty-two of 33 subjects (67%) had electrophysiological evidence of macular dysfunction without generalized retinal dysfunction. Disease-causing variants were found in 31 patients (31/40, 78%). There was a higher prevalence of the variant p.Arg2030Gln in the cohort with foveal sparing compared to the group with foveal atrophy (6.45% vs 1.07%). CONCLUSIONS The distinct clinical and molecular characteristics of patients with the foveal-sparing phenotype are described. The presence of 2 distinct phenotypes of Stargardt disease (foveal sparing and foveal atrophy) suggests that there may be more than 1 disease mechanism in ABCA4 retinopathy.

The IS/OS Junction Layer in the Natural History of Type 2 Idiopathic Macular Telangiectasia

PURPOSE To document the progression of a break in the photoreceptor inner segment/outer segment (IS/OS) junction layer and its functional correlates over time in the natural history of type 2 idiopathic macular telangiectasia (type 2 MacTel). METHODS Patients with at least 1 year of follow-up were selected from the MacTel Study. En face images were created by manual segmentation of the IS/OS junctional line in volume scans acquired using a spatial-domain optical coherence tomography retinal imaging unit. Retinal sensitivity thresholds were determined using a retinal microperimeter unit. Aggregate retinal sensitivity loss within IS/OS lesions was calculated. Changes over time in an area of IS/OS defects and retinal sensitivity were analyzed. RESULTS thirty-nine eyes of 23 patients (mean age: 62.3 ± 9.2 years) were analyzed. Mean follow-up time was 1.9 years (range: 1-3 years). Mean IS/OS break area at baseline was 0.575 mm(2) (SE = 0.092, 95% confidence interval [CI]: 0.394-0.756 mm(2)). The cluster-adjusted mean annual progression rate in IS/OS break area was 0.140 mm(2) (SE = 0.040, 95% CI: 0.062-0.218 mm(2), P < 0.001). Mean aggregate retinal sensitivity loss was at baseline 28.56 dB (SE = 5.43, 95% CI: 17.32-39.80 dB, n = 28), a positive correlation with IS/OS lesion area was present (P < 0.001). The mean annual rate of change in aggregate sensitivity loss was 5.14 dB (SE = 1.51, 95% CI: 2.19-8.10 dB, P < 0.001, n = 37), a significant correlation with lesion area increase was found (P = 0.006). CONCLUSIONS Both IS/OS break area and rate of enlargement correlate with aggregate retinal sensitivity loss in type 2 MacTel. En face OCT imaging of the IS/OS layer provides a functionally relevant method for documenting disease progression in type 2 MacTel.

Optical Coherence Tomography Angiography for Anterior Segment Vasculature Imaging

PURPOSE To evaluate the application of an optical coherence tomography angiography (OCTA) system adapted for the assessment of anterior segment vasculature. DESIGN Cross-sectional, observational study. PARTICIPANTS Consecutive subjects with normal eyes on slit-lamp clinical examination and patients with abnormal corneal neovascularization. METHODS All scans were performed using a commercially available AngioVue OCTA system (Optovue, Inc., Fremont, CA) using an anterior segment lens adapter and the split-spectrum amplitude decorrelation angiography algorithm. Each subject underwent scans from 4 quadrants (superior, inferior, nasal, and temporal) in each eye by 2 trained, independent operators. MAIN OUTCOME MEASURES Analysis of signal strength, image quality, and reproducibility of corneal vascular measurements was performed. RESULTS In our study of 20 normal subjects (10 men, 10 women; mean age, 25.3±7.8 years), we found good repeatability (κ coefficient, 0.76) for image quality score and good interobserver agreement for vasculature measurements (intraclass coefficient, 0.94). After optimization of the angiography scan protocol, vascular measurements within the regions of interest were compared in the superior versus inferior quadrants (mean vascular loops, 3.34±1.16 vs. 3.12 ± 0.90 [P = 0.768]; segment-to-loop ratio, 4.18±0.71 vs. 4.32±0.87 [P = 0.129]; fractal dimension [Df] value, 1.78±0.06 vs. 1.78±0.06 [P = 0.94]; vascular loop area, 25.9±14.5 vs. 25.9±10.7 × 10(-3) mm(2) [P = 0.21]) and nasal versus temporal quadrant (mean vascular loops, 2.89±0.98 vs. 3.57±0.99 [P < 0.001]; segment-to-loop ratio, 3.94±0.69 vs. 4.55±0.78 [P = 0.897]; Df value, 1.78±0.06 vs. 1.77±0.06 [P = 0.14]; vascular loop area, 29.7±15.7 vs. 22.1±7.1 × 10(-3) mm(2) [P = 0.38]. We then used the established OCTA scanning protocol to visualize abnormal vasculature successfully in 5 patients with various corneal pathologic features, including graft-associated neovascularization, postherpetic keratitis scarring, lipid keratopathy, and limbal stem cell deficiency. CONCLUSIONS This preliminary study describes a method for acquiring OCTA images of the cornea and limbal vasculature with substantial consistency. This technique may be useful for the objective evaluation of corneal neovascularization in the future.

Repeatability and Reproducibility of Choroidal Vessel Layer Measurements in Diabetic Retinopathy Using Enhanced Depth Optical Coherence Tomography

PURPOSE To describe novel segmentation protocols for choroidal layers, Sattlers medium and Hallers large vessel layers, using enhanced depth imaging optical coherence tomography (EDI-OCT), and to examine the repeatability and reproducibility of these measurements in eyes with diabetic retinopathy. METHODS Fifty-one patients with Type 2 diabetes mellitus were imaged using custom EDI scanning protocols. Detailed segmentation was performed to quantify the retina, choroid, Hallers large, and Sattlers medium vessel layers in the total macular circle (TMC) and foveal central subfield (FCS). The coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were used as a measure of repeatability and relative reliability within graders. Reproducibility or interobserver variability was assessed using Bland-Altman plots and 95% limits of agreement (LoA). RESULTS Intragrader CR of the retina, choroid, Sattlers, and Hallers layers for thickness measurements were 19.2, 26.9, 35.2, and 29.2 μm, respectively. Intergrader 95% LoA were 27.9, 41.5, 38.6, 31.1 μm (thickness), respectively. Choroidal sublayer measurements showed good intraobserver reliability (ICC 0.78-0.98). Interobserver variability for retinal and choroidal measurements was not significantly different (P > 0.45). Measurements from the TMC showed slightly better repeatability and agreement compared with the FCS alone. Mean intergrader differences were reduced after training, and were most apparent in choroidal sublayers. CONCLUSIONS The choroidal vascular sublayers can be quantified with good reliability, repeatability, and reproducibility. Accurate quantitative assessment of these sublayers may provide new insights into the role of the choroid in visual loss in patients with diabetic retinopathy, and prove useful for future clinical trials.

Clinical course and treatment outcomes of Sorsby fundus dystrophy.

PURPOSE To analyze the natural history of Sorsby fundus dystrophy and the effect of various treatment methods for choroidal neovascularization (CNV) in this dystrophy. DESIGN Historical cohort study. METHODS A cohort of 42 patients with the Ser181 Cys TIMP3 mutation were identified from the electronic database of genetic retinal diseases in Moorfields Eye Hospital. Retrospective analyses of case records were carried out. Serial best-corrected visual acuity, fundus findings, age at onset of CNV, initial location of CNV, time taken for CNV to progress to subfoveal location, and the interval between development of CNV in the first and second eye were recorded. The time taken for CNV to recur to a subfoveal location in patients in whom argon laser photocoagulation was carried out for extrafoveal CNV also was documented. In cases where photodynamic therapy (PDT) was carried out for subfoveal CNV, the visual outcome, number of PDT treatments, and progression of lesion size were noted. RESULTS The median age at onset of CNV in the first eye was 46.1 years and in the second eye was 50.3 years. The mean interval between the development of CNV in the first and second eye was 4.5 years. The median age at which vision fell to 20/200 or below was 48 years (first eye) and 54 years (second eye). Argon laser therapy and PDT are not effective in treating CNV of patients with this dystrophy. Antiangiogenic agents may be more effective in this condition. CONCLUSIONS The main cause of blindness resulting from this dystrophy is CNV. Antiangiogenic agents may be useful in preventing visual loss as a result of this condition.

Systematic Evaluation of Optical Coherence Tomography Angiography in Retinal Vein Occlusion.

PURPOSE To evaluate the clinical utility of optical coherence tomography angiography (OCTA) in patients with retinal vein occlusion (RVO), and to systematically compare OCTA images with changes seen on color fundus photography and fluorescein angiography (FA). DESIGN Reliability analysis. METHODS Eighty-one eyes of 76 patients with a history of RVO (branch, central, or hemicentral), both acute and chronic, underwent OCTA and color fundus photography. In 29 eyes, data were compared to FA imaging. Comparative and multimodal analysis of the 3 imaging procedures were performed. RESULTS We identified good agreement between FA and OCTA scans centered on the macula for capillary nonperfusion (intraclass correlation coefficient [ICC] 0.825 for the 3 × 3-mm scan and 0.891 for the 8 × 8-mm scan). Agreement for area of capillary changes (dilation, pruning, and telangiectasia) was also substantial (ICC 0.712 for the 3 × 3-mm scan and 0.787 for the 8 × 8-mm scan). For foveal avascular zone grading, agreement was good for the 3 × 3-mm scan (kappa = 1.000 for radius and kappa = 0.799 for outline) but poor for the 8 × 8-mm scan (kappa = 0.156 for radius and kappa = 0.600 for outline). The quality of the images obtained was an important issue for OCTA, as 15.1% of scans were nongradable, particularly in patients unable to maintain fixation. CONCLUSIONS OCTA is a quick, reliable, and noninvasive method to evaluate the area of capillary nonperfusion and foveal avascular zone morphology in patients with RVO. However, good fixation is a requirement for acquisition of good-quality images.