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# Which Early Sign Sees It Coming
- URL: https://www.swisseyemd.com/which-early-sign-sees-it-coming/
- Published: 2026-09-09T06:00:06.000Z
- Updated: 2026-09-09T06:00:06.000Z
- Description: iRORA names the stage before geographic atrophy, and consensus offered its progression as a trial measure. Followed over time, a different early OCT sign predicts progression better, and one two readers agree on more readily.
- Author: Miguel Castilla
- Tags: The Atrophy Arc

The last entry ended on a worry. If the feature that gives cRORA its name is also the one two readers agree on least, then some of what we call progression is the reader moving and not the lesion. That worry only matters because of what comes after it. We read these early signs in order to act early, and acting early assumes the sign tells us where the eye is going. Reproducibility was the first condition. Prediction is the one that earns it. Before we can ask which early signs predict, we have to name the stage that sits before the endpoint, the one this arc has kept in view and never defined.

That stage is incomplete RPE and outer retinal atrophy, iRORA, set out by the Classification of Atrophy Meetings in their fourth report. On OCT it carries the same elements as the complete form: a region of hypertransmission into the choroid, a zone of attenuation or disruption of the RPE, and evidence of overlying photoreceptor degeneration. What holds it short of cRORA is extent. The hypertransmission and the RPE loss are present but do not yet reach the 250 micron thresholds, or they appear in patches rather than as one continuous zone, with no scrolled RPE or other sign of a tear to explain the picture. It is atrophy that has begun and not finished. As with everything in this arc, the term describes an imaging phenotype and does not settle what the cells beneath it are doing.

![Two-panel schematic cross-section of the retina. Left (iRORA, incomplete): the RPE band has small interrupted gaps with a narrow faint column of hypertransmission below. Right (cRORA, complete): one wide continuous break in the RPE, a broad bright column of hypertransmission into the choroid, and collapse of the overlying retinal layers](https://storage.ghost.io/c/0e/7b/0e7b0c0e-ac22-42d2-aef9-0c07388f00c5/content/images/2026/09/Gemini_Generated_Image_k7mf2kk7mf2kk7mf.jpg)

 Figure 1\. The same three OCT features define both stages; extent separates them. In iRORA the hypertransmission and RPE loss are present but discontinuous and below the 250 µm thresholds; in cRORA a single wide break in the RPE, a broad column of hypertransmission and collapse of the overlying retina meet them. Schematic illustration, not an OCT scan. Criteria: *Guymer RH, et al. CAM Report 4, Ophthalmology 2020;127(3):394-409; Sadda SR, et al. Report 3, Ophthalmology 2018;125(4):537-548.*

Naming a precursor is a claim in disguise. To call iRORA incomplete is to assert that it lies on the road to the complete form, an earlier point on a single trajectory, and the consensus proposed exactly that. It proposed too that progression from iRORA to cRORA might serve as a measure in trials that want to act before vision is lost. A definition cannot prove its own claim. Whether iRORA actually forecasts progression, and how well, is a question for eyes followed over time.

One such cohort comes from the same group. 280 eyes of 140 people, all with large drusen in both eyes and none with advanced disease at the start, were imaged with OCT and photographed every six months for up to three years. The endpoint they tracked was geographic atrophy on colour fundus photography, the historical reference standard, and a coarser instrument than the OCT criteria we have been discussing. On that endpoint iRORA carried weight. Eyes with iRORA, whether present at baseline or appearing later, reached geographic atrophy at an adjusted hazard ratio of 12.1 relative to eyes without it, with a confidence interval running from 1.5 to 99.8\. **The precursor we had just finished defining did raise the risk of progression, which is the reassuring half of the result.** The other half is where it becomes interesting.

Alongside iRORA the same eyes were graded for a second early sign, nascent geographic atrophy. It is defined by subsidence of the inner nuclear and outer plexiform layers, or by a hyporeflective wedge within Henle's fibre layer, and readers of the last entry will recognise those features. They were among the signs two graders agreed on most readily, well above the RPE margin that gives iRORA its edges. Tested against the same endpoint, nascent atrophy carried an adjusted hazard ratio of 78.6, though with a confidence interval from 13.7 to 415.1 that should temper any precision read into that figure. The decisive comparison came when both signs were placed in one model. Nascent atrophy held its association with progression; iRORA lost its own, its independent contribution falling away once the other sign was accounted for, to a P value of 0.52\. Measured by how much of the timing to atrophy each sign explained, nascent atrophy accounted for roughly 91% and iRORA 43%. **The signs we agreed on most readily in** [**the last entry**](https://www.swisseyemd.com/what-two-readers-can-agree-on/) **are also the signs that predict best, and they sit outside the definition of iRORA.**

![Forest plot on a logarithmic axis. iRORA: adjusted hazard ratio 12.1 (95% CI 1.5–99.8), variance explained 43%. Nascent GA: adjusted hazard ratio 78.6 (95% CI 13.7–415.1), variance explained 91%. A dashed line marks no effect at 1](https://storage.ghost.io/c/0e/7b/0e7b0c0e-ac22-42d2-aef9-0c07388f00c5/content/images/2026/09/Gemini_Generated_Image_m6ogpbm6ogpbm6og.jpg)

Figure 2\. Two early OCT signs against the same endpoint, progression to geographic atrophy on colour fundus photography, in 280 eyes followed for up to three years. Nascent GA carried a higher adjusted hazard ratio than iRORA (78.6 vs 12.1) and explained more of the variance in time to atrophy (91% vs 43%); with both signs in one model, only nascent GA remained significant (iRORA P=0.52). The wide confidence intervals reflect the modest number of events. Data: *Wu Z, et al. Ophthalmology 2023;130:205-212 (Results; Table 2).*

None of this tells us what to do about either sign, and it is not meant to. What it does is sharpen the target. A trial that hopes to act before atrophy is established needs an entry criterion that both readers can apply and that genuinely marks eyes on their way to the endpoint. A sign that is reproducible and predictive is worth more for that purpose than one that is neither reliably read nor independently informative once a stronger sign is in the room. Whether acting at this stage changes the course of the disease is a separate question, and the established lesion and its first treatments are where the next entry goes.

Which leaves an uncomfortable possibility to sit with. The consensus named iRORA as the incomplete stage and offered its progression as something trials might measure, yet in these eyes the sign that saw atrophy coming was the subsidence of the deeper layers, a change that sits outside what defines iRORA. If the precursor we chose to name is not the precursor that predicts, how confident should we be that we are watching the right sign at all?

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**References**

1. Guymer RH, Rosenfeld PJ, Curcio CA, et al. Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4\. *Ophthalmology.* 2020;127(3):394-409.
2. Wu Z, Goh KL, Hodgson LAB, Guymer RH. Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy: Longitudinal Evaluation in Age-Related Macular Degeneration. *Ophthalmology.* 2023;130(2):205-212.
3. Wu Z, Luu CD, Ayton LN, et al. Optical coherence tomography-defined changes preceding the development of drusen-associated atrophy in age-related macular degeneration. *Ophthalmology.* 2014;121(12):2415-2422.
4. Sadda SR, Guymer R, Holz FG, et al. Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3\. *Ophthalmology.* 2018;125(4):537-548.

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