Renata Portella Nunes

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.

Predicting the progression of geographic atrophy in age-related macular degeneration with SD-OCT en face imaging of the outer retina.

BACKGROUND AND OBJECTIVE Spectral-domain optical coherence tomography (SD-OCT) en face imaging was used to measure the growth of geographic atrophy (GA) and identify baseline anatomic changes in the outer retina in eyes with nonexudative age-related macular degeneration (AMD). PATIENTS AND METHODS In this prospective study, eyes were imaged using 200 × 200 and 512 × 128 A-scan raster patterns. Outer retinal anatomy was visualized using en face imaging of a 20-μm thick slab encompassing the inner segment/outer segment (IS/OS) band. RESULTS En face SD-OCT imaging of the IS/OS region revealed a bilaterally symmetrical pattern of outer retinal disruption extending beyond the borders of GA that accurately predicted the progression of GA over 1 year in 13 of 30 eyes (43.3%). In the remaining cases, the area of disruption was much larger than the area of progression. CONCLUSION En face imaging of the outer retina can predict the growth of GA in some eyes. Due to the bilateral symmetry of these findings, this imaging strategy may identify a genetic subset of patients in whom photoreceptor loss precedes the progression of GA. These areas with outer retinal disruption should be followed in clinical trials designed to test treatments for dry AMD.

Spectrum of Retinal Vascular Diseases Associated With Paracentral Acute Middle Maculopathy.

PURPOSE To evaluate the spectrum of retinal diseases that can demonstrate paracentral acute middle maculopathy and isolated ischemia of the intermediate and deep capillary plexus. DESIGN Retrospective, multicenter, observational case series. METHODS This is a retrospective case series review of 9 patients (10 eyes) from 5 centers with paracentral acute middle maculopathy lesions and previously unreported retinal vascular etiologies. Case presentations and multimodal imaging, including color photographs, near-infrared reflectance, fluorescein angiography, spectral-domain optical coherence tomography (SD OCT), and orbital color Doppler imaging, are described. Baseline and follow-up findings are correlated with clinical presentation, demographics, and systemic associations. RESULTS Five men and 4 women, aged 27-66 years, were included. Isolated band-like hyperreflective lesions in the middle retinal layers, otherwise known as paracentral acute middle maculopathy, were observed in all patients at baseline presentation. Follow-up SD OCT analysis of these paracentral acute middle maculopathy lesions demonstrated subsequent thinning of the inner nuclear layer. Novel retinal vascular associations leading to retinal vasculopathy and paracentral acute middle maculopathy include eye compression injury causing global ocular ischemia, sickle cell crisis, Purtschers retinopathy, inflammatory occlusive retinal vasculitis, post-H1N1 vaccine, hypertensive retinopathy, migraine disorder, and post-upper respiratory infection. CONCLUSION Paracentral acute middle maculopathy lesions may develop in a wide spectrum of retinal vascular diseases. They are best identified with SD OCT analysis and may represent ischemia of the intermediate and deep capillary plexus. These lesions typically result in permanent thinning of the inner nuclear layer and are critical to identify in order to determine the cause of unexplained vision loss.

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.

Response to Aflibercept After Frequent Re-treatment With Bevacizumab or Ranibizumab in Eyes With Neovascular AMD

BACKGROUND AND OBJECTIVE To evaluate the effects of switching to aflibercept in eyes with neovascular age-related macular degeneration (AMD) requiring frequent re-treatment with bevacizumab or ranibizumab. PATIENTS AND METHODS Retrospective review of 73 eyes of 65 patients with neovascular AMD switched to aflibercept due to persistent or recurrent macular fluid after at least 1 year of intravitreal bevacizumab or ranibizumab with re-treatment at least every 6 weeks. Minimum post-switch follow-up was 6 months. All patients were treated using a treat-and-extend strategy. The treatment intervals immediately after and before the switch were the same. RESULTS The mean pre-switch anti-VEGF therapy duration was 45 months, and the mean number of injections was 31. In the 6 months after the switch, the average number of injections was reduced by 0.6 compared with the 6 months before the switch (P < .001). Visual acuity was unchanged during this period (P = .78). Central retinal thickness (CRT) decreased by 19 µm after the switch (P < .001). Seventy eyes had vascularized retinal pigment epithelial detachments (PEDs). The decrease in the PED cube-root volume during the 6 months after the switch was statistically significant (-0.07 mm; P = .007). CONCLUSION The number of injections, CRT, and PED volume decreased significantly after the switch to aflibercept, but visual acuity was unchanged.

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.

Optical coherence tomography measurements of choroidal thickness in healthy eyes: Correlation with age and axial length

BACKGROUND AND OBJECTIVE To evaluate subfoveal choroidal thickness (CT) in healthy eyes using spectral-domain optical coherence tomography (SD-OCT) and provide correlations between age and axial length. PATIENTS AND METHODS Enhanced depth SD-OCT imaging was performed with Cirrus (Carl Zeiss Meditec, Dublin, CA) and Spectralis (Heidelberg Engineering, Heidelberg, Germany) instruments. CT was measured from the outer limit of the retinal pigment epithelium to the inner surface of the sclera. RESULTS The study enrolled 155 patients, with at least 20 in each decade between 22 and 89 years old. Mean axial length was 23.6 mm. Mean Heidelberg subfoveal CT was 286 µm. The correlation between Heidelberg and Zeiss subfoveal CT measurements was strong (r = .978) and significant (P < .001). Mean subfoveal CT was 7.7 µm thinner by Heidelberg versus Cirrus (P < .001). Multiple linear regression analysis revealed that age (P < .001), axial length (P = .001), and sex (P = .025) were significantly related to Heidelberg subfoveal CT. CONCLUSION There is a strong negative correlation between CT and age (P <.001), with a 25 µm decrease in CT for each decade of life. Increasing axial length demonstrated a negative correlation with CT, decreasing 24.9 µm for each mm of axial length. Future studies of CT measurements can be performed on either instrument and must account for axial length, age, and sex to make appropriate conclusions.

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.