Outer Retinal Tubulation (ORT) is a form of photoreceptor reorganization that occurs during the degenerative process of the outer retina. It is formed when degenerated photoreceptors arrange into circular to tubular structures.
ORT is most commonly observed in age-related macular degeneration (AMD), but also appears in various chronic degenerative retinal diseases such as geographic atrophy (GA), retinitis pigmentosa (RP), Stargardt disease, choroideremia, and angioid streaks.
In neovascular age-related macular degeneration, the cumulative incidence of ORT increases over time, with CATT analysis reporting rates of 17% at 1 year, 28% at 2 years, 35% at 3 years, and 41% at 4 years 1). ORT is treated as an OCT finding indicating chronic degeneration.
The main related diseases are listed below.
| Disease category | Representative diseases |
|---|---|
| Degenerative diseases | Neovascular age-related macular degeneration, geographic atrophy, Stargardt disease |
| Retinal dystrophy | Retinitis pigmentosa, choroideremia |
| Other | Angioid streaks |
ORT is most commonly found in neovascular age-related macular degeneration. It also appears in various diseases that cause chronic outer retinal degeneration, such as geographic atrophy, retinitis pigmentosa, Stargardt disease, choroideremia, and angioid streaks.
ORT itself has no specific subjective symptoms. Visual acuity loss, metamorphopsia, and central scotoma due to the underlying disease (neovascular age-related macular degeneration, GA, etc.) are prominent. It is known that eyes with ORT have poorer visual acuity and retinal sensitivity compared to eyes without ORT.
SD-OCT is the primary detection method. En face OCT and AOSLO (adaptive optics scanning laser ophthalmoscopy) also provide characteristic images.
SD-OCT Findings
Hyperreflective border: Forms a clear hyperreflective boundary wall within the outer nuclear layer (ONL).
Hyporeflective space: The interior of the boundary is observed as a hyporeflective space.
Shape: Round to oval, observed as single or multiple lesions.
En face OCT
Branching network: En face images show a network-like pattern of tubular structures that branch and anastomose.
Three-dimensional understanding: The three-dimensional extent of ORT can be assessed by comparison with tomographic images.
AOSLO findings
Visualization of photoreceptor arrangement: The tubular arrangement of remaining photoreceptors can be directly observed at high resolution.
Research use: Currently, its use is primarily in clinical research.
In neovascular age-related macular degeneration, the presence of ORT has been reported as an indicator of poor visual acuity and chronic disease 1). In eyes with GA, ORT-positive eyes tend to have a slower rate of GA enlargement.
Eyes with ORT have poorer visual acuity and retinal sensitivity than eyes without ORT, serving as an indicator of visual function decline. Since it is not a sign of exudative activity itself, the need for anti-VEGF treatment should be determined based on other findings such as fluid accumulation and hemorrhage 1).
ORT forms against a background of degeneration and atrophy of the outer retinal layers. The following factors are associated with the risk of ORT development.
SD-OCT is the basis of diagnosis. It identifies round to oval hyporeflective spaces with hyperreflective borders within the ONL. Combining en face OCT allows three-dimensional understanding of the extent of the tubular network.
ORT must be differentiated from other similar intraretinal findings. It is clinically important to avoid unnecessary treatment due to misidentification.
| Finding | Hyperreflective border | Location | Activity |
|---|---|---|---|
| ORT | Present | ONL (outer layer) | Inactive |
| CME (cystoid macular edema) | Absent | Inner to outer layer | Active |
| IRF (intraretinal fluid) | None | Inner layer | Active |
| SRF (subretinal fluid) | None | Subretinal | Active |
If mistaken for cystoid macular edema, there is a risk of unnecessary anti-VEGF treatment or steroid administration. ORT is an inactive degenerative finding and is not a treatment target. Confirming the presence or absence of highly reflective boundaries on SD-OCT is key to differentiation (see “Standard Treatment” section).
ORT itself has no direct treatment. ORT is an indicator of inactive degeneration and is not a target for therapeutic intervention.
The basis of management is appropriate control of the underlying disease.
ORT is formed as a result of outer retinal degeneration. It is thought that due to RPE damage and atrophy, photoreceptor cells lose adhesion, and the remaining photoreceptors fold inward to form tubular structures. This tubular arrangement may provide a survival advantage for photoreceptors over the atrophic RPE.
Small hyporeflective spaces appear within the outer nuclear layer (ONL). The external limiting membrane (ELM) begins to function as a boundary.
Tubular structures become distinct, with highly reflective tube walls. The walls are composed of the ELM and mitochondria of the photoreceptor inner segments. En face OCT shows a branching network pattern.
Cellular elements within the lumen decrease, and the hyporeflective space expands. The surrounding ONL also progressively thins.
ORT disappears or transforms into scar-like hyperreflective foci. Atrophy of the RPE and Bruch’s membrane becomes severe.
Localization
ONL level: Formed in the outer nuclear layer (outer nuclear cell body layer).
ELM demarcation: The external limiting membrane (ELM) functions as the outer wall of the lumen.
Structure
Radial photoreceptors: Photoreceptors are arranged radially along the inner wall of the lumen.
Tubular wall components: Composed of ELM and photoreceptor inner segment mitochondria.
Fundamental Lesion
Subjacent RPE degeneration: RPE degeneration and atrophy exist directly beneath the lumen.
EZ disruption: Often accompanied by disruption or loss of the ellipsoid zone (EZ).
Hyperreflective foci (HRF) have been reported to appear prior to EZ disruption and outer segment shortening3), and may reflect the degenerative process of the outer retina as a precursor to ORT.
In the early stage, low-reflectance spaces appear within the outer nuclear layer, and in the mature stage, tubular structures with highly reflective walls become established. In the degenerative stage, the lumen expands and the surrounding ONL becomes thinner, and in the end stage, the structure disappears or becomes scarred. At each stage, degeneration of the RPE and Bruch’s membrane also progresses in parallel.
In the CATT analysis by Lee et al., ORT in neovascular age-related macular degeneration increased over time and was shown to be an indicator of chronic lesions and visual function decline 1). However, treatment response should not be determined by ORT alone; interpretation in conjunction with exudative and atrophic findings is necessary.
Arrigo A et al. used multimodal imaging (OCT, OCTA, DART OCTA) to comprehensively classify cystoid findings in eyes with neovascular age-related macular degeneration and proposed criteria for differentiating ORT from degenerative pseudocysts with similar morphology 2). This approach is expected to be applied to imaging AI.
In a scoping review by Mat Nor et al., the clinical significance of HRF was organized for ocular diseases including age-related macular degeneration, diabetic retinopathy, and glaucoma. HRF is attracting attention as an imaging biomarker reflecting the progression of outer retinal degeneration 3). Further research on its relationship with ORT is ongoing.
