Carlos Alexandre de Amorim Garcia Filho

Systemic Complement Inhibition with Eculizumab for Geographic Atrophy in Age-Related Macular Degeneration: The COMPLETE Study

PURPOSE To evaluate the effect of eculizumab, a systemic inhibitor of complement component (C5), on the growth of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). DESIGN Prospective, double-masked, randomized clinical trial. PARTICIPANTS Patients with GA measuring from 1.25 to 18 mm(2) based on spectral-domain optical coherence tomography imaging. METHODS Patients were randomized 2:1 to receive intravenous eculizumab or placebo over 6 months. In the eculizumab treatment arm, the first 10 patients received a low-dose regimen of 600 mg weekly for 4 weeks followed by 900 mg every 2 weeks until week 24, and the next 10 patients received a high-dose regimen of 900 mg weekly for 4 weeks followed by 1200 mg every 2 weeks until week 24. The placebo group was infused with saline. Patients were observed off treatment for an additional 26 weeks. Both normal-luminance and low-luminance visual acuities were measured throughout the study, and the low-luminance deficits were calculated as the difference between the letter scores. MAIN OUTCOME MEASURES Change in area of GA at 26 weeks. RESULTS Thirty eyes of 30 patients were enrolled. Eighteen fellow eyes also met inclusion criteria and were analyzed as a secondary endpoint. For the 30 study eyes, mean square root of GA area measurements ± standard deviation at baseline were 2.55 ± 0.94 and 2.02 ± 0.74 mm in the eculizumab and placebo groups, respectively (P = 0.13). At 26 weeks, GA enlarged by a mean of 0.19 ± 0.12 and 0.18 ± 0.15 mm in the eculizumab and placebo groups, respectively (P = 0.96). At 52 weeks of follow-up, GA enlarged by a mean of 0.37 ± 0.22 mm in the eculizumab-treated eyes and by a mean of 0.37 ± 0.21 mm in the placebo group (P = 0.93, 2 sample t test). None of the eyes converted to wet AMD. No drug-related adverse events were identified. CONCLUSIONS Systemic complement inhibition with eculizumab was well tolerated through 6 months but did not decrease the growth rate of GA significantly. However, there was a statistically significant correlation between the low-luminance deficit at baseline and the progression of GA over 6 months.

Comparison of Geographic Atrophy Measurements from the OCT Fundus Image and the Sub-RPE Slab Image

PURPOSE To compare two different approaches to measuring areas of geographic atrophy (GA) using spectral-domain optical coherence tomography (SD-OCT). METHODS Fifty eyes with GA were imaged with an SD-OCT instrument. OCT fundus images and sub- retinal pigment epithelium (RPE) slab images were generated. Three graders manually drew the GA boundaries on both en face images. An automated algorithm was used to segment the GA boundaries from the sub-RPE slabs. RESULTS The agreement between the three manual measurements on both OCT fundus images (ICC = .998) and sub-RPE slabs (ICC = .999) was excellent. Area measurements from OCT fundus images and sub-RPE slabs were highly correlated. The agreement between manual and automated measurements on the sub-RPE slabs was very good (ICC = .795). CONCLUSION Both OCT fundus images and sub-RPE slab images proved useful for measuring GA in age-related macular degeneration. The automated algorithm typically provided useful measurements of GA area from the sub-RPE slabs.

Change in drusen volume as a novel clinical trial endpoint for the study of complement inhibition in age-related macular degeneration.

BACKGROUND AND OBJECTIVE To evaluate the change in drusen volume following treatment with eculizumab, a systemic inhibitor of complement component 5. PATIENTS AND METHODS Single-center, prospective, randomized, double-masked clinical trial. Patients were randomized 2:1 to receive intravenous eculizumab or placebo over 26 weeks. MAIN OUTCOME MEASURE decrease in drusen volume of at least 50% at 26-week follow-up. RESULTS Mean drusen cube root volumes were 0.49 mm and 0.47 mm (P = .64) at baseline and 0.51 mm and 0.42 mm (P = .17) at 26 weeks in the eculizumab and placebo groups, respectively. In the placebo group, one eye had a decrease in drusen volume of at least 50% and two eyes developed neovascularization through 26 weeks. CONCLUSION Systemic complement inhibition with eculizumab did not significantly reduce drusen volume. Drusen growth was dependent on the number of complement at-risk alleles. Future trials should consider the use of a composite clinical trial endpoint in which efficacy is defined by the treatment’s ability to prevent drusen growth, neovascularization, and the formation of geographic atrophy over 1 year.

Comparison of geographic atrophy growth rates using different imaging modalities in the COMPLETE study

BACKGROUND AND OBJECTIVE To compare the measurements and growth rates of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) obtained using different imaging modalities. PATIENTS AND METHODS Thirty patients with AMD and GA measuring from 1.25 mm² to 18 mm² based on spectral-domain optical coherence tomography (SD-OCT) fundus imaging were enrolled. Imaging was performed at baseline and at follow-up months 3, 6, 9, and 12, including autofluorescence (AF) imaging with a fundus camera-based flash system (TRC-50DX; Topcon Medical Systems, Oakland, NJ; AF excitation λ: 535-585 nm; detection λ: 605-715 nm), AF and fluorescein angiography (FA) imaging with a confocal scanning laser ophthalmoscopy (SLO) system (Spectralis; Heidelberg Engineering, Heidelberg, Germany; AF excitation λ: 488 nm; detection λ: > 500 nm), and SD-OCT en face imaging (Cirrus; Carl Zeiss Meditec, Dublin, CA). RESULTS Average baseline square root measurements and enlargement rates of square root areas appeared similar across all modalities; 0.2 mm was the largest difference between any pair of measurement means. The intraclass correlation coefficients (ICC) were essentially equal to 1 for all comparisons of area measurements but were lower for growth rates than area measurements. Comparison of 26-week average enlargement rates showed no significant difference between the SLO AF image and enhanced SD-OCT en face image (mean difference: 0.01 mm; SD: 0.10; P = .70). CONCLUSION Agreement among all imaging modalities in measuring the areas of GA at baseline diminished when the growth rates of GA were compared over 26 weeks, likely because each imaging technique identifies different anatomic features along the border of GA, which may appear similar but change at different rates.

Quantitative changes in retinal pigment epithelial detachments as a predictor for retreatment with anti-VEGF therapy.

Purpose: To determine if quantitative changes in retinal pigment epithelial detachments (PEDs) predict the need for retreatment in eyes undergoing spectral domain optical coherence tomography (SD OCT)–guided as-needed therapy with anti–vascular endothelial growth factor drugs. Methods: Patients with vascularized PEDs undergoing SD OCT–guided treatment with anti–vascular endothelial growth factor drugs were retrospectively identified. The decision to retreat these cases was based on qualitative assessments of fluid in the macula. Spectral domain OCT images from visits in which the treatment was withheld were retrospectively analyzed. A novel algorithm was then used to measure the area and volume of PEDs at these visits. Results: Fourteen eyes were identified, and retreatment was withheld at 57 visits. When the SD OCT algorithm was used to evaluate the scans from these visits, the PED volume increased at eight visits. At all of these eight visits, a treatment was needed at the next follow-up visit. For the remaining 49 visits in which the treatment was withheld, the PED volume did not increase and no treatment was needed at the next follow-up visit. Conclusion: Quantitation of the change in the PED volume and area may be useful in determining when to retreat eyes undergoing SD OCT–guided as-needed anti–vascular endothelial growth factor therapy.

Optic coherence tomography in a patient with diffuse unilateral subacute neuroretinitis

PURPOSE To measure retinal nervous fiber layer (RNFL) thickness using OCT3 (Carl-Zeiss) in patients with diffuse unilateral subacute neuroretinitis (DUSN) with or without live worm and correlate it with visual acuity. METHODS RNFL thickness, using RNFL thickness 3.4 program and best corrected visual acuity were measured in patients with DUSN between January 2005 and December 2006. RESULTS Thirty-eight patients, aged 9 - 42 years were selected, of whom 20 had live worm. Mean RNFL was 71.55 +/- 27.26 in the DUSN eye and 103.07 +/- 20.66 in the contralateral eye (p<0.001). Pearsons correlation between visual acuity and RNFL was r= -0.522 (p<0.001) in the DUSN eye and r= -0.097 (p=0.509) in the contralateral eye. CONCLUSION RNFL thickness in DUSN patients is directly proportional to visual acuity. Further research is needed to reinforce the correlation between visual acuity and thickness of the nerve fibers in patients with DUSN to follow them after the treatment.

Association Between Subfoveal Choroidal Thickness, Reticular Pseudodrusen, and Geographic Atrophy in Age-Related Macular Degeneration

BACKGROUND AND OBJECTIVE To compare subfoveal choroidal thickness (CT) measurements in eyes with nonexudative age-related macular degeneration (AMD) in the presence or absence of reticular pseudodrusen (RPD). PATIENTS AND METHODS Subfoveal CT measurements obtained from patients with AMD enrolled in the COMPLETE study (30 drusen-only eyes and 30 eyes with geographic atrophy [GA]) were compared with an age-distributed normal control group. Multimodal images were evaluated to detect the presence of RPD. RESULTS After controlling for age and axial length, the mean CT was significantly thinner in the GA group with RPD (213.7 ± 53.1 µm) than in the GA group without RPD (335.3 ± 123.2 µm; P = .001). The mean CT in the GA group without RPD was not statistically different from the mean CT in the normal control group (P = .076) or the drusen group without RPD (P = .45). In eyes without RPD, there was a correlation between the increasing size of GA and a decrease in CT measurements. CONCLUSION Subfoveal choroidal thinning in eyes with nonexudative AMD was associated with the presence of RPD. In the absence of RPD, CT only decreased as the size of GA increased.

OCT Minimum Intensity as a Predictor of Geographic Atrophy Enlargement

PURPOSE We determined whether the minimum intensity (MI) of the optical coherence tomography (OCT) A-scans within the retina can predict locations of growth at the margin of geographic atrophy (GA) and the growth rate outside the margin. METHODS The OCT scans were analyzed at baseline and 52 weeks. Expert graders manually segmented OCT images of GA. The 52-week follow-up scans were registered to the baseline scan coordinates for comparison. The OCT MI values were studied within a 180-μm margin around the boundary of GA at baseline. Baseline MI values were compared in areas of progression and nonprogression of the GA, and sensitivity and specificity were assessed for prediction of growth at the margin. Average MI values in the margins were compared to overall growth rates to evaluate the prediction of growth outside the margins. RESULTS A statistically significant increase in MI (P < 0.05) was seen in areas of growth in 21/24 cases (88%), and 22/24 cases (92%) when the foveal subfield was excluded. Locations of growth within the margins at 52 weeks were predicted with 61% sensitivity and 61% specificity. The MI values correlated significantly with overall growth rate, and high and low growth rate subjects were identified with 80% sensitivity and 64% specificity. CONCLUSIONS The MI may be increased at the margins of GA lesions before enlargement, which may indicate disruption or atrophy of the photoreceptors in these areas before GA becomes apparent. Increased MI may help predict areas of enlargement of GA, and may relate to overall growth rate and be a useful screening tool for GA. (ClinicalTrials.gov number, NCT00935883.).

Change in drusen area over time compared using spectral-domain optical coherence tomography and color fundus imaging

PURPOSE To investigate the relationship between drusen areas measured with color fundus images (CFIs) and those with spectral-domain optical coherence tomography (SDOCT). METHODS Forty-two eyes from thirty patients with drusen in the absence of geographic atrophy were recruited to a prospective study. Digital color fundus images and SDOCT images were obtained at baseline and at follow-up visits at 3 and 6 months. Registered, matched circles centered on the fovea with diameters of 3 mm and 5 mm were identified on both CFIs and SDOCT images. Spectral-domain OCT drusen measurements were obtained using a commercially available proprietary algorithm. Drusen boundaries on CFIs were traced manually at the Doheny Eye Institute Image Reading Center. RESULTS Mean square root drusen area (SQDA) measurements for the 3-mm circles on the SDOCT images were 1.451 mm at baseline and 1.464 mm at week 26, whereas the measurements on CFIs were 1.555 mm at baseline and 1.584 mm at week 26. Mean SQDA measurements from CFIs were larger than those from the SDOCT measurements at all time points (P = 0.004 at baseline, P = 0.003 at 26 weeks). Changes in SQDA over 26 weeks measured with SDOCT were not different from those measured with CFIs (mean difference = 0.014 mm, P = 0.5). CONCLUSIONS Spectral-domain OCT drusen area measurements were smaller than the measurements obtained from CFIs. However, there were no differences in the change in drusen area over time between the two imaging modalities. Spectral-domain OCT measurements were considerably more sensitive in assessing drusen area changes.

Spectral-Domain Optical Coherence Tomography Measurements of Choroidal Thickness and Outer Retinal Disruption in Macular Telangiectasia Type 2

BACKGROUND AND OBJECTIVE To evaluate subfoveal choroidal thickness (CT) and the extent of outer retinal disruption in patients with macular telangiectasia type 2 (MacTel2) compared with healthy eyes. PATIENTS AND METHODS In this prospective, observational, cohort study, 62 patients (62 eyes) with Mac-Tel2 and 130 healthy controls (130 eyes) underwent a complete ophthalmological examination, spectral-domain optical coherence tomography (SD-OCT) imaging, and axial length measurements. Patients in the study group also underwent color fundus photography, fundus autofluorescence, and fluorescein angiography. En face SD-OCT imaging was used to assess abnormalities involving the photoreceptor inner segment/outer segment/ellipsoid zone (IS/OS/EZ). RESULTS After adjusting for age and axial length, the authors found that eyes with MacTel2 had a mean CT measurement that was greater than control eyes (P = .007). There was a negative correlation between the visual acuity and the area of IS/OS/EZ damage (P = .009), but no statistically significant correlation was seen between CT and the area of IS/OS/EZ damage. CONCLUSION Eyes with MacTel2 were found to have thicker CT measurements than control eyes. While the extent of IS/OS/EZ disruption correlated with the loss of visual acuity, this damage did not correlate with CT measurements.