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Patient presents for management of wet AMD
Tubule-like structures were seen on optical coherence tomography of the left eye.
We present the case of an 82-year-old man with a history of diabetic retinopathy and age-related macular degeneration in both eyes. He was referred to our clinic to transfer care for neovascular AMD in the left eye, with multiple prior anti-VEGF injections.
The patient’s vision was 20/40+2 in the right eye and 20/60+2 in the left eye with normal IOP. He was pseudophakic in both eyes. Anterior segment examination in each eye was otherwise unremarkable.
Fundus examination in the right eye showed quiescent proliferative diabetic retinopathy and pigmentary changes associated with non-neovascular AMD. In contrast, the left macula had pigmentary changes, a patch of retinal pigment epithelium (RPE) atrophy and a trace amount of subretinal hemorrhage.
Spectral-domain optical coherence tomography (Spectralis, Heidelberg Engineering) was performed. The OCT was non-contributory in the right eye, but the left eye showed irregularity of the RPE and disruption of the IS/OS junction. There were multiple ring-shaped tubule-like lesions, with hyperreflective borders surrounding a hyporeflective lumen, located in the outer retinal layer (Figure 1).
Pear Pongsachareonnont
The diagnosis was active wet AMD in the left eye, and the patient received treatment over the next year and a half with intravitreal injections of Avastin (bevacizumab, Genentech) and Eylea (aflibercept, Regeneron Pharmaceuticals). During this time, the visual acuity in the left eye remained stable at 20/60+2. Fundus examination remained stable, and OCT showed no change in the tubulation pattern (Figure 2).
Figure 1. Multiple ring-shaped lesions with hyperreflective outlines in the outer retina with disruption of the IS/OS layer (thick arrows). A small cystoid lesion was also present in the central macula (thin arrow).
Images: Pongsacharaeonnont P, Stewart JM
Figure 2. Tubular lesions in the outer retina over a 19-month follow-up period. There was no change in the number or shape of these lesions.
Discussion
Recent improvements in the resolution of OCT have improved clinicians’ ability to identify the different layers and components of the retina. This has yielded new morphologic changes that can be detected by SD-OCT that had not been observed with time- domain OCT. An example of this is outer retinal tubulation (ORT), also known as outer retinal cysts (ORC), as seen in our patient and has been observed in patients with neovascular AMD. This lesion has not been reported in patients with early or intermediate AMD. The incidence of tubulation is reported to be 24.2% in AMD patients and is more common in neovascular AMD (56%) than atrophic AMD (20.7%). The finding has also been observed in choroidal neovascularization associated with pseudoxanthoma elasticum, multifocal choroiditis and panuveitis with CNV, geographic atrophy, central serous chorioretinopathy, Bietti’s crystalline dystrophy, choroideremia and other retinal degenerations.
Outer retinal tubulation can be described as round or oval hyporeflective spaces with a hyperreflective ring border on OCT sections in the outer nuclear layer, sometimes connected to the subretinal space. A hyperreflective material is often present in the lumen of the tubule, which is thought to consist of deranged photoreceptor outer segments, although the pathogenesis is not known. Zweifel and colleagues, who named this finding ORT, proposed that it is a rearrangement of the photoreceptor layer in response to retinal injury. A possible mechanism of ORT development begins with minor injury to photoreceptors, which leads to loss of the interdigitation of the outer segments and RPE degeneration. This results in loss of tight junctions and disruption of other points of attachment to neighboring neural elements followed by outward folding of the photoreceptor layer, allowing the formation of new lateral tight junction connections, which leads to the formation of tubular structures, possibly as part of a reparative process.
Another hypothesis was proposed by Wolff and colleagues, who described this cystic structure as ORC. They hypothesized that ORC results from the fusion of several multinucleated giant cell macrophages in AMD. These macrophages carry out phagocytosis between the inner collagenous layer of Bruch’s membrane and the basement membrane of the RPE. Recently, Wolff and colleagues published a case series of neovascular AMD by en face OCT and found the same tubulation features as described by Zweifel and colleagues. They also described two characteristics of tubulation patterns in exudative and atrophic AMD. Exudative AMD patients with ORT showed a branching pseudodendritic pattern reminiscent of a dendritic cell, whereas atrophic AMD cases showed common ORT patterns around the margin of the atrophic zone, which they called perilesional.
ORT can be found in the macula and other regions of the retina, but it usually occurs in areas of normal retinal thickness near areas of healthier photoreceptor layers. In an eye with a history of anti-VEGF treatment, ORT is typically found in an area that previously had intraretinal or subretinal fluid. If there is no CNV, it can present where areas of intact and absent IS/OS junction meet.
It is important for clinicians to be able to recognize ORT and distinguish it from cystoid macular edema on OCT imaging because this directly affects decision making for additional anti-VEGF injections. Unlike CME, ORT structures are surrounded by a hyperreflective border, and the lumen can contain material with variable hyperreflectivity.
Over a follow-up period ranging from 3 months to 3 years, ORT structures mostly remain stable during a course of treatment with anti-VEGF injections, as in our patient. However, in some cases, a decrease in height of the tubules and tubule diameter after treatment has been seen, but this did not correlate with visual improvement.
In conclusion, ORT is believed to result from a healing process in the outer retina after disease-related injury. It is commonly found in neovascular AMD but also can present in other conditions affecting the outer retina. Future improvements in imaging technology may help us to better understand the natural history and prognosis of this finding.