Outer Retinal Tubulation as a Predictor of the Growth Rate of Geographic Atrophy in Age Related Macular Degeneration Amirhossein Hariri 1, Muneeswar G. Nittala 1, Erin Henry 2, Erich C. Strauss 2, Phillip Lai 2, SriniVas R. Sadda 1 1. Doheny Eye Institute, Doheny Image Reading Center, Los Angeles, CA 2. Genentech, Inc., South San Francisco, California. The growth amount of GA at 18 months for all eyes was calculated, and the rates were compared between eyes with ORT and eyes without ORT. To eliminate the effect of initial lesion size on the growth amount of GA, a square root transformation (SQRT) was applied to the GA area prior to comparisons. Purpose Results One hundred forty-three patients had images collected at baseline. Of those 143 patients, 108 had fellow eye imaging data available at Month 18, and were included in this analysis. The area of GA on OCT as determined by the two graders showed excellent agreement, with an intraclass correlation coefficient of 0.99 (95% CI: 0.99-1.00). In the 84 eyes without evidence of ORT, the mean and median total area of GA was 6.27 and 5.85 mm2 at the baseline, increasing to 8.93 and 9.45 mm2 at the month 18 visit. In 24 eyes with ORT, the mean and median total area of GA was 8.10 and 7.75 mm2 at the baseline visit, increasing to 9.95 and 9.85 mm2 at the month 18 visit. The Difference between the initial size of GA lesion in eyes with and without ORT was not statistically significant. (P=0.08) The novel optical coherence tomographic finding of outer retinal tubulation (ORT) in advanced diseases affecting the outer retina and the retinal pigment epithelium (RPE) was first identified in 2009. These ORT lesions were identified as branching tubular structures in the outer nuclear layer of the retina in en face OCT scans, and appeared as round or ovoid hyporeflective spaces with hyperreflective borders on OCT B-scans. It was speculated that ORTs formed as a result of a sublethal injury to the photoreceptors. To further evaluate the significance of ORT, we studied the impact of ORT on the progression of geographic atrophy (GA) in age related macular degeneration (AMD). Methods The MAHALO study (NCT01229215) enrolled 143 subjects into a Phase Ib/II multicenter, randomized, single-masked, sham-injection controlled clinical trial of the safety, tolerability and evidence of activity of lampalizumab in patients with bilateral GA associated with AMD. Spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence images were obtained at multiple time points in both eyes, but this analysis only considered the fellow/non-study eyes. All OCT B-scans as well as en face images at the level of the outer nuclear layer (generated using the Advanced Visualization function of the Cirrus HD-OCT review software, version 6.0.2) at baseline and month18, were reviewed by two independent, masked graders for the presence of ORT (Fig 1).The results from the two graders were compared, and for discrepant cases, the two graders met in open adjudication to arrive at a consensus result. Grading of GA areas at baseline and Month 18 visits was also performed using the FDA-cleared Advanced RPE Analysis Tool which is available in Cirrus HD-OCT review software. Initial correction of all segmentation errors was performed by one grader (AH), and then GA areas were calculated (Fig 2). To evaluate the reproducibility of GA area grading, a second grader (MGN) re-graded 30% of cases in a masked fashion.   Full cohort (108 eyes) Eyes with multifocal GA (61eyes) Eyes with single GA lesion (47 eyes) No ORT (84 eyes) ORT (24 eyes) p value (49 eyes) (12 eyes) (35 eyes) GA Growth in mm2 2.67 ± 1.61 1.85 ± 0 .78 0.001 2.91 ± 1.70 2.08 ± 0 .88 0.01 2.24 ± 1.40 1.63 ± 0.57 0.02 Growth of SQRT of GA in mm 0.56 ± 0.38 0.33 ± 0.11 <0.001 0.65 ± 0.42 0.34 ± 0.14 0.40 ± 0.20 0.31 ± 0.09 0.03 Fig 1: ORTs as seen on a B-scan (top) and on an en face image (bottom) Conclusions In eyes with ORT, GA lesions appear to enlarge at a significantly slower rate than that of eyes without ORT. The presence of ORT may need to be accounted for in longitudinal studies of geographic atrophy. Financial Interest: Dr Sadda has the following financial disclosures: Carl Zeiss Meditec (C,F), Allergan (C,F), Genentech (C,F), Optos (C,F), Optovue (F). MAHALO Study sponsored by Genentech. Fig 2: Geographic atrophy automatically graded by Advanced RPE Analysis software (Top images), and segmentation after adjustment by certified grader (bottom images).