Alexander C. Walsh

Quantitative Subanalysis of Optical Coherence Tomography after Treatment with Ranibizumab for Neovascular Age-Related Macular Degeneration

PURPOSE To investigate the effects of ranibizumab on retinal morphology in patients with neovascular age-related macular degeneration (AMD) using optical coherence tomography (OCT) quantitative subanalysis. METHODS Data from 95 patients receiving intravitreal ranibizumab for neovascular AMD were collected. StratusOCT images were analyzed using custom software that allows precise positioning of prespecified boundaries on every B-scan. Changes in thickness/volume of the retina, subretinal fluid (SRF), subretinal tissue (SRT), and pigment epithelial detachments (PEDs) at week 1 and at months 1, 3, 6, and 9 after treatment were calculated. RESULTS Total retinal volume reached its nadir at month 1, with an average reduction of 0.43 mm(3) (P < 0.001). By month 9, this initial change had been reduced to a mean reduction of 0.32 mm(3) (P = 0.0011). Total SRF volume reached its lowest level by month 1, with an average reduction of 0.24 mm(3) (P < 0.001). This reduction lessened subsequently, to 0.18 mm(3), by month 9. There was an average 0.3-mm(3) decrease in total PED volume by month 1 (P < 0.001), and this later declined further, to 0.45 mm(3), by month 9 (P = 0.0014). Total SRT volume was reduced by an average of 0.07 mm(3) at month 1 (P = 0.0159) and subsequently remained constant. CONCLUSIONS Although neurosensory retinal edema and SRF showed an early reduction to nadir after the initiation of ranibizumab therapy, the effect on the retina was attenuated over time, suggesting possible tachyphylaxis. PED volume showed a slower but progressive reduction. Manual quantitative OCT subanalysis may allow a more precise understanding of anatomic outcomes and their correlation with visual acuity.

Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation

Aims To evaluate the effect of switching to bevacizumab or ranibizumab after developing tachyphylaxis during anti-vascular endothelial growth factor (VEGF) therapy for choroidal neovascularisation (CNV). Methods The authors reviewed the records of all patients who received both ranibizumab and bevacizumab for treatment of CNV to identify those who developed tachyphylaxis, defined as optical coherence tomography evidence of initial decreased exudation followed by lack of further reduction or an increase in exudation. Signs of exudation included subreitnal fluid (SRF), pigment epithelial detachment (PED) and/or cystoid macular oedema (CMO). Results 26 eyes were included. 10 were initially treated with bevacizumab and then changed to ranibizumab for persistent SRF, PED and/or CMO. Of these, seven had occult CNV and three had predominantly classic CNV. One eye in the occult CNV group did not respond after being switched to ranibizumab. Six eyes had a positive therapeutic response, after one injection in four eyes, and after two or three injections in one eye each. In the classic group, two responded to ranibizumab and one did not. Sixteen eyes were initially treated with ranibizumab before changing to bevacizumab. Of these, 15 had occult CNV and 1 was predominantly classic. Three of the 16 eyes failed to respond to bevacizumab; 6 improved after one injection and 5 after two injections. Conclusions Patients with CNV who develop tachyphylaxis to ranibizumab or bevacizumab may respond to another anti-VEGF drug. The majority of cases (81%) in this series demonstrated at least some response after switching therapies.

Spatial distribution of posterior pole choroidal thickness by spectral domain optical coherence tomography.

PURPOSE To study the spatial distribution of posterior pole choroidal thickness (CT) in healthy eyes using spectral domain optical coherence tomography (SD-OCT). METHODS Fifty-nine eyes from 30 subjects with no retinal or choroidal disease were examined with high-definition (HD) OCT using macular volume cube scanning protocols. A randomly chosen subset also had multifield analysis performed (volume scans centered on and surrounding the optic nerve head [ONH]). CT was manually quantified using a validated reading center tool. For macular scans, mean CT was calculated for each Early Treatment Diabetic Retinopathy Study subfield. Compound posterior pole CT maps were also created through the alignment of OCT projection images. Regression analyses were used to evaluate the correlation between CT and axial length (AL), refractive error, age, sex, and ethnicity. RESULTS Subfoveal CT was 297.8 ± 82.2 μm, which did not differ significantly from that of the inner macular subfields. CT was greatest in the superior outer subfield and thinnest in the nasal outer subfield. The most predictive models for macular CT included AL and/or age. Outside the macula, CT was thinnest inferonasal to the ONH. CONCLUSIONS CT demonstrates large variations between individuals, but also at different locations within the posterior pole; substantial choroidal thinning inferonasal to the ONH was demonstrated. CT appears to correlate more with distance from the optic nerve than from the fovea and, thus, in future studies, the ONH may serve as a better reference point than the foveal center for expressing or depicting regional CT variations.

Quantitative optical coherence tomography findings in various subtypes of neovascular age-related macular degeneration.

PURPOSE To compare the volume of various spaces visible on optical coherence tomography (OCT) images in different angiographic lesion subtypes of neovascular age-related macular degeneration (AMD). METHODS Sixty-six cases of previously untreated, active subfoveal choroidal neovascularization (CNV) associated with AMD were retrospectively collected. CNV lesions were classified as occult with no classic CNV, minimally classic CNV, predominantly classic CNV, or CNV lesions with associated retinal angiomatous proliferation (RAP). Corresponding OCT image sets were analyzed by trained graders using previously validated custom software that allows manual placement of boundaries on OCT B-scans. Spaces delineated by these boundaries included the neurosensory retina, subretinal fluid, subretinal tissue, and pigment epithelial detachments (PEDs). Volume measurements were calculated by the software and compared among groups. RESULTS Minimally and predominantly classic CNV membranes demonstrated subretinal tissue on OCT in all cases and appeared to show a significantly greater volume of subretinal tissue than did the occult membranes. Subretinal fluid was present in all the predominantly classic cases. A PED was visible in all the occult CNV cases in our study, demonstrating less retinal thickening and significantly greater PED volumes than minimally and predominantly classic CNV lesions. Lesions associated with RAP showed the highest percentage of cystoid spaces. CONCLUSIONS OCT and angiography provide complementary information regarding CNV lesions. Quantitative analysis of OCT images allows for an improved understanding of the anatomic characteristics of angiographically defined CNV lesion subtypes.

Accuracy of retinal thickness measurements obtained with Cirrus optical coherence tomography

Aim: To report the frequency and severity of retinal thickness measurement errors in a Fourier domain optical coherence tomography (FDOCT) device, Cirrus OCT. Methods: Data from 209 eyes undergoing Cirrus OCT imaging with the Macular Cube protocol were collected. For each eye, the position of the automated retinal boundary lines used by the Cirrus OCT software for thickness calculations was assessed using a 6-point categorical scale. The presence of errors was correlated with various parameters including: retinal morphological features and disease diagnosis. Results: Errors of retinal boundary detection were observed in 57.5% of eyes but were severe in only 9.6% of eyes. The identification of subretinal fluid, subretinal tissue, pigment epithelium detachment or a diagnosis of choroidal neovascularisation was associated with more severe errors. Retinal cysts or a diagnosis of retinal vascular disease were less likely to be associated with significant error. Conclusions: Retinal thickness measurement errors appear to occur less frequently with Fourier domain OCT (Cirrus OCT), but segmentation errors remain a concern, particularly in assessment of eyes with structurally complex retinal disease. With the recent release of multiple FDOCT systems, assessment of segmentation error may be an important factor in determining the relative merits of these systems.

Quantitative Subanalysis of Cystoid Spaces and Outer Nuclear Layer Using Optical Coherence Tomography in Age-Related Macular Degeneration

PURPOSE To use optical coherence tomography (OCT) to quantify intraretinal cystoid spaces (ICSs) and the outer nuclear layer (ONL) in patients with neovascular age-related macular degeneration (AMD) and to investigate the correlation of these parameters with visual acuity. METHODS StratusOCT (Carl Zeiss Meditec, Inc., Dublin, CA) images were collected from 53 patients receiving their initial treatment with intravitreous ranibizumab. Images were analyzed with custom software (OCTOR) that allows accurate manual segmentation of OCT B-scans and provides thickness/volume measurements of ICS, ONL, neurosensory retina, pigment epithelial detachments (PEDs), subretinal fluid (SRF), and subretinal tissue (SRT). Univariate and multivariate analyses were used to correlate OCT parameters with best corrected Snellen visual acuity. Reproducibility was assessed with weighted kappa statistics and intraclass correlation coefficients. RESULTS A multivariate linear regression model with adjusted R(2) showed that ONL volume and SRT thickness significantly correlated with Snellen visual acuity (R(2) = 0.15, P = 0.002 and R(2) = 0.19, P = 0.001, respectively) with an overall model R(2) of 0.34. Adjustment of ONL volume for ICS did not improve correlation with visual acuity, and ICS volume did not independently correlate with visual acuity. Weighted kappa statistics showed excellent intergrader agreement for both ICS and ONL measurements. CONCLUSIONS The results suggest that an increased total volume of the ONL is associated with decreased visual acuity in neovascular AMD and that the total volume of ICS does not correlate with visual acuity. Although the correlations detected in this study are modest, quantitative subanalysis of OCT images may be of greater clinical relevance in the context of more advanced OCT technology.

Comparison of the optical coherence tomographic features of choroidal neovascular membranes in pathological myopia versus age-related macular degeneration, using quantitative subanalysis

Aim: To compare the retinal morphological characteristics of eyes with choroidal neovascularisation (CNV) secondary to pathological myopia versus eyes with CNV secondary to age-related macular degeneration (AMD), using quantitative optical coherence tomography (OCT) subanalysis. Methods: Twenty-one eyes of 21 patients newly diagnosed as having CNV secondary to pathological myopia, and 43 consecutive cases of eyes with newly diagnosed subfoveal CNV secondary to AMD were retrospectively collected. In all patients, StratusOCT images and fluorescein angiograms (FA) were available for analysis. StratusOCT images were analysed using custom software (termed “OCTOR”), which allowed calculation of the thickness/volume of the neurosensory retina, subretinal fluid (SRF), subretinal tissue (SRT) and pigment epithelial detachments (PEDs). FA images were used to calculate CNV leakage area and CNV lesion size for each eye. Results: The total volume of neurosensory retina in the pathological myopia group was significantly less than in the AMD group (7.10 (SD 0.50) mm3 vs 7.76 (0.93) mm3, p = 0.004). The total volume of SRF in the pathological myopia group was less than in the AMD group, but the difference was not statistically significant (0.33 (1.38) mm3 vs 0.55 (0.82) mm3, p = 0.434). The total volume of SRT in the pathological myopia group was less than in the AMD group, but the difference was not statistically significant (0.16 (0.15) mm3 vs 0.36 (0.60) mm3, p = 0.144). The total volume of PED in the pathological myopia group was markedly less than in the AMD group (0.01 (0.03) mm3 vs 1.09 (1.89) mm3, p<0.001). On FA, the total leakage of CNV in the AMD group was significantly greater than in the pathological myopia group (4.17 (3.29) DAs vs 0.53 (0.58) DAs, p<0.001). Conclusions: CNV lesions in pathological myopia were associated with considerably less retinal oedema, SRF and SRT compared with CNV associated with AMD. PEDs were almost negligible in myopic lesions compared with AMD. These findings are consistent with previous clinical and angiographic descriptions of myopic CNV as relatively small lesions with modest exudation.

Evaluation of Optical Coherence Tomography Retinal Thickness Parameters for Use in Clinical Trials for Neovascular Age-Related Macular Degeneration

PURPOSE To investigate the relationship between automated and manually derived measurements of central retinal thickness from optical coherence tomography (OCT) and to determine the relationship between the foveal center point (FCP) and the foveal central subfield (FCS) in neovascular age-related macular degeneration (AMD). METHODS Data were collected from 216 patients with newly diagnosed neovascular AMD, who underwent StratusOCT imaging at diagnosis. Raw StratusOCT images for each patient were analyzed with the publicly available custom software OCTOR, which allows accurate manual grading of OCT B-scans. Manually derived central retinal thickness measurements were compared with measurements obtained from automated StratusOCT analysis. Manually obtained measurements of FCP and FCS were also compared. RESULTS The mean (+/-SD) difference in thickness between automated and manually derived FCP thickness was 7.9 microm (+/-90.8), but the maximum difference was 455 microm. The limits of agreement (95% confidence interval), between automated and manually obtained FCP thicknesses, were -173.7 microm (lower limit) and 189.6 microm (upper limit), with a coefficient of determination (R(2)) of 0.49 (P < 0.001). In contrast, the R(2) for manually derived FCP and manually derived FCS thickness was 0.94 (P < 0.001), with a smaller mean (+/-SD) difference in thickness of 13.8 microm (+/-29.8). CONCLUSIONS Manual correction of errors in automated OCT segmentation may be necessary for accurate interpretation of anatomic outcomes for clinical trials of neovascular AMD. In addition, although measurement of FCS remains preferable for assessment of central retinal thickness, accurate measurement of FCP may represent an adequate alternative when FCS is unavailable.

Detection of Cystoid Macular Edema with Three-Dimensional Optical Coherence Tomography versus Fluorescein Angiography

PURPOSE To compare the sensitivity and reproducibility of three-dimensional optical coherence tomography (3D-OCT) and fluorescein angiography (FA) for the detection of cystoid macular edema (CME). METHODS Data were retrospectively collected from all patients who underwent digital FA and 512 × 128 horizontal raster 3D-OCT scans on the same day in a retina subspecialty clinic. Images were reviewed independently by four reading center graders and adjudicated as a group to render a single result for each eye and each imaging modality. The κ statistic was used to determine the level of agreement between graders for each modality. The sensitivity of each imaging modality for CME detection was calculated by using the presence of CME on either modality as the ground truth; subgroup analysis was performed according to disease diagnosis and lens status. RESULTS Four hundred thirteen eyes of 207 patients were included in the analysis. Intergrader agreement was higher for 3D-OCT than for FA both before (κ(OCT) = 0.61, κ(FA) = 0.43) and after adjudication (κ(OCT) = 0.74, κ(FA) = 0.58).The sensitivity for detection of definite CME was higher for 3D-OCT (95%, 144/151 cases) than for FA (44%, 67/151 cases). Definite FA (+) 3D-OCT (-) CME was identified in 1 eye (0.2%), whereas definite FA (-) 3D-OCT (+) CME was identified in 40 eyes (10%). No significant associations between CME detection and lens examination or disease diagnosis were observed. CONCLUSIONS In this study, 3D-OCT was more sensitive and had better intergrader agreement than did FA for the detection of CME.

Relationship between outer retinal thickness substructures and visual acuity in eyes with dry age-related macular degeneration.

PURPOSE To explore the correlation between outer retinal substructures and visual acuity in dry age-related macular degeneration (AMD). METHODS Analysis of spectral domain optical coherence tomography datasets from 100 eyes of 100 consecutive patients with dry AMD was performed. The internal limiting membrane, outer nuclear layer (ONL), external limiting membrane (ELM), inner segment-outer segment (IS-OS) junction, outer photoreceptor border, inner and outer retinal pigment epithelium (RPE) borders, and Bruchs membrane, were manually segmented by Doheny Image Reading Center (DIRC) graders. Areas, thicknesses, and volumes of RPE, IS, OS, ONL, and the total retina in the foveal central subfield were correlated with the logarithm of minimal angle of resolution (logMAR) visual acuity using univariable and multivariable regression analysis. RESULTS The visual acuity in this group ranged from logMAR 0 to 1.3 with a mean of 0.23. Areas, thicknesses, and volumes of ONL, IS and OS, thicknesses of total retinal and RPE, and intensities of IS, OS, and RPE, showed statistically significant association (P < 0.05) with logMAR best corrected visual acuity. The highest correlations were observed for the ONL (thickness: r = -0.49, volume: -0.47, area: -0.50) and photoreceptor IS (thickness: -0.59, area: -0.63, volume: -0.53). The model with the highest correlation in this study included thicknesses of ONL, IS, OS and RPE, as well as area of ONL, IS, OS, RPE, and intensity of RPE. CONCLUSIONS. Although integrity of outer retinal substructures in the foveal central subfield correlates with visual acuity in the eyes of patients with dry AMD, the correlation is only moderate and does not fully explain the variability in acuity in these cases.