The advent of spectral domain optical coherence tomography (SD-OCT) has led to superb imaging capabilities in addition to enhanced visualization of the retinal anatomy. The noninvasive technology of SD-OCT coupled with faster imaging speeds, wide-field capabilities, and greater depth resolution has greatly enhanced our ability to image retinal microarchitecture. Such advancements have led to the identification of a variety of new retinal conditions, including outer retinal tubulations. Zweifel et al. first observed outer retinal tubulations in 2009 on SD-OCT as well-delineated ovoid hyporeflective areas with a surrounding hyperreflective border located specifically in the outer nuclear layer in patients with age-related macular degeneration.1 Although the pathogenesis of outer retinal tubulations remains unclear, it seems to involve injury to the retinal pigment epithelium and/or photoreceptors leading to a compensatory reorganization of the viable photoreceptors with the neighboring photoreceptors. Outer retinal tubulations were initially linked to wet age-related macular degeneration (AMD); however, recent studies have shown a myriad of retinal disorders, degenerations, and dystrophies associated with these anomalous structures. Perhaps any disease entity that can lead to apoptosis, degeneration, or damage to the outer retinal tissue can result in outer retinal tubulation formation within the retina.
The identification of outer retinal tubulations may indeed prove to be useful in determining the severity, chronicity, and perhaps the prognosis of the disease. Our cases will highlight the wide variety of clinical presentations and etiologies associated with outer retinal tubulation. The case presentations will include two cases of wet age-related macular degeneration, a case of presumed ocular histoplasmosis, a case of central areolar choroidal dystrophy, and a case of pathological myopia.
An 80-year-old white female patient presented with a history of blurry vision in the right and left eyes for the past few years. The patient’s ocular history included wet AMD and primary open-angle glaucoma in both eyes. The patient reported receiving multiple intravitreal injections (Lucentis, ranibizumab) in both eyes a few years before for the treatment of wet macular degeneration; however, the number of treatments was unknown. Her systemic history included atrial fibrillation and diabetes type 2, controlled with Metoprolol and an unknown diabetic medication, respectively. Her best-corrected visual acuity was count fingers at 2 feet in both eyes. Her pupils revealed a 1+ afferent pupillary defect in the left eye. Confrontation visual fields and extraocular motilities were limited because of poor visual acuity in both eyes. Her intraocular pressure measured 10 mmHg in the right eye and 12 mmHg in the left eye. The anterior segment included a patent laser peripheral iridotomy and a posterior chamber intraocular lens in both eyes. All other anterior segment findings were unremarkable. The fundus examination showed glaucomatous cupping of the optic nerve in both eyes, specifically a cup to disc ratio of 0.85:0.85 (vertical/horizontal) in the right eye, and 1.0:1.0 in the left eye with mild peripapillary atrophy in both eyes. The macula exhibited an area of large disciform scarring, greater in the right eye, with retinal pigment epithelium hyperplasia and retinal pigment epithelium atrophy in both eyes (Fig. 1A, B). The peripheral retina was flat and intact without diabetic retinopathy in both eyes. SD-OCT revealed a small ovoid area with a hyperreflective border in the outer retina consistent with outer retinal tubulation in both eyes (Fig. 1C, D). The patient was educated on her retinal condition and advised to continue using an Amsler grid to monitor the condition, taking vitamins for the eye containing lutein and zeaxanthin, and nutritional recommendations including green leafy vegetables. The patient was advised to return to the clinic in 3 months for follow-up or sooner if any visual changes were noticed.
An 85-year-old male patient presented to the clinic with complaints of decreased vision in the left eye for the past 4 years. The patient had a history of unilateral open-angle glaucoma in the right eye since 2006, controlled with timolol 0.5% twice a day in the right eye. The patient had a history of a serous retinal detachment in the left eye in 2010 and wet macular degeneration in 2011 for which he received multiple intravitreal injections but later stopped treatment in 2013 because of persistent ocular pain. The patient’s medical history included congestive heart failure, diabetes mellitus type 2, and hypertension, which were controlled with Glipizide, Carvedilol, and Lisinopril. Upon examination, the patient reported paracentral wavy lines inferiorly in the left eye on Amsler grid. The best-corrected visual acuity was 20/60 in the right eye and count fingers at 4 feet in the left eye. Pupillary testing revealed sluggish pupils in both eyes, and we were unable to obtain confrontation visual fields and motility as the patient was a poor responder for both tests. The anterior segment examination revealed mild nuclear and cortical lenticular changes in both eyes. The intraocular pressures were 17 mmHg in the right eye and 18 mmHg in the left eye. The posterior segment revealed asymmetric optic nerve cupping, specifically, a cup to disc ratio of 0.6:0.4 in the right eye and 0.4:0.4 in the left eye both flat, sharp, and with good color. However, the right optic nerve had nerve fiber layer thinning inferiorly and superiorly. The fundus showed drusen with disruption of the retinal pigment epithelium in the macula of the right eye and macular thickening in the left eye (Fig. 2A, B). SD-OCT showed multiple areas of retinal pigment epithelium disruption from associated drusen and many focal areas of disruption in the ellipsoid zone in the right eye (Fig. 2C). SD-OCT showed an abnormal foveal architecture with intraretinal fluid, retinal pigment epithelium atrophy, and oval lesions in the outer retina consistent with outer retinal tubulations in the left eye (Fig. 2D). The peripheral retina was normal without diabetic retinopathy. The patient was referred to a retinal specialist for further evaluation and possible OCT and fluorescein angiography.
A 73-year-old white female patient presented to the clinic with complaints of wavy black lines in her right eye for the past week. The patient had an ocular history of cataract surgery bilaterally 10 years ago and a history of an “ocular infection associated with bleeding in the left eye” 30 years ago. The patient’s medical history consisted of hypertension and high cholesterol, controlled with Losartan and Simvastatin, respectively. Her best-corrected visual acuity was 20/30 in the right eye and 20/400 in the left eye. Preliminary testing was unremarkable. However, Amsler grid testing revealed paracentral metamorphopsia superiorly and inferiorly in the right eye, and a large central scotoma in the left eye. Slit-lamp examination of the anterior segment revealed a posterior chamber intraocular lens in good position with trace posterior capsular haze in both eyes. The optic nerve cup to disc ratio was 0.3:0.3 in the right eye and 0.25:0.25 in the left eye. The optic nerve was flat, sharp, and with good color in both eyes. The posterior segment revealed peripapillary atrophy in both eyes. Macular evaluation of the right eye showed an epiretinal membrane associated with a pseudohole (Fig. 3A). The macula of the left eye showed a large area of disciform scarring with retinal pigment epithelium atrophy (Fig. 3B). SD-OCT of the right eye revealed an epiretinal membrane and small central drusenoid pigment epithelial detachment with adjacent parafoveal subretinal fluid. The left eye showed intraretinal fibrosis with associated disorganization of the retinal architecture, retinal pigment epithelium atrophy, and small ovoid outer retinal lesions characteristic of outer retinal tubulation (Fig. 3C). Note that the pseudohole architecture does not appear on this particular SD-OCT scan of the left eye, but is visible in the fundus photograph (Fig. 3B). The peripheral examination revealed isolated punched out areas of pigment epithelial atrophy in the mid-periphery of both eyes consistent with presumed ocular histoplasmosis syndrome. The patient was referred to a retinal specialist for treatment for the choroidal neovascular membrane in the right eye.
A 48-year-old white male patient presented to the clinic for a low vision evaluation. He had been diagnosed by a local retinal specialist with geographic dry AMD in both eyes and was taking Preservision supplements. His medical history was remarkable for hypertension, depression, and anxiety, for which he was being treated with Terbinafine and Trazadone. Best-corrected visual acuity was 20/60 in the right eye and 20/100 in the left eye. The intraocular pressures were 17 mmHg in the right eye and 18 mmHg in the left eye. All entrance testing was unremarkable, and all anterior segment findings were normal in both eyes. Dilated fundus examination revealed healthy optic nerves with a cup to disc ratio of 0.2:0.2 in both eyes. The macula was remarkable for central areas of retinal pigment epithelium and choroidal atrophy (Fig. 4A, B), while the peripheral retina was unremarkable in both eyes. These findings were consistent with central areolar choroidal dystrophy. SD-OCT scans revealed significant retinal pigment epithelium atrophy, photoreceptor disruption, and retinal thinning with outer retinal tubulation noted in both eyes (Fig. 4C, D). Because of the previous diagnosis of geographic AMD, the patient was referred to a different retinal specialist who agreed with a diagnosis of central areolar choroidal dystrophy. The patient was ultimately provided with low vision aids and counseled regarding the nature of his condition and the genetic implications.
A 48-year-old female patient presented for follow-up. She had recently undergone bilateral cataract surgery and suffered from open-angle glaucoma and pathological degenerative myopia in both eyes. Her medical history was significant for hypertension, diabetes type 2, and obstructive sleep apnea. Medications included timolol 0.5% and dorzolamide twice a day in both eyes, insulin, hydrocodone, an unknown diabetes medication, an unknown hypertension medication, and Ativan. Best-corrected visual acuity was 20/50 in the right eye and 20/150 in the left eye, and applanation tonometry revealed intraocular pressures of 21 in the right eye and 22 in the left eye. Pupil and extraocular motility testing were unremarkable, whereas automated visual field testing revealed central and arcuate scotomas that were both greater in the left eye. Anterior segment findings with slit-lamp examination revealed floppy eyelids in both eyes and a well-centered posterior chamber intraocular lens in both eyes. Dilated fundus examination revealed significant optic nerve head cupping with loss of temporal rim tissue in both eyes. The cup to disc ratio was 0.9:0.9 in the right eye and 0.9:0.8 in the left eye. The macula in both eyes exhibited severe myopic atrophy, degeneration, and staphylomatous changes (Fig. 5A, B). The peripheral retina was significant for myopic degeneration in both eyes. SD-OCT scans exhibited staphylomas with outer retinal tubulations in both eyes (Fig. 5C, D). The patient’s glaucoma medications were adjusted, but she did not return for further follow-up.
Outer retinal tubulation can occur as a result of multiple degenerative retinal diseases, dystrophies, and degenerations. Outer retinal tubulation was first recognized in association with macular degeneration; however, outer retinal tubulation has recently been documented in many other retinal conditions. It is speculated that outer retinal tubulations occur as a result of an abnormal reparative process whereby the retinal photoreceptors degenerate and fold inwardly in an attempt to establish connections with viable photoreceptor inner and outer segments. Conditions like AMD cause injury to the retinal pigment epithelium and overlying photoreceptors, which results in a separation between the layers and allows for tissue invagination to occur.2 The understanding of the pathophysiology of outer retinal tubulations can provide insight into the etiology of associated conditions and possible information regarding the natural progression and prognosis of the particular disease.
The most common disease entity associated with outer retinal tubulations is wet AMD. The development of choroidal neovascular membranes results either directly from an inflammatory-mediated angiogenic drive or secondary to a degenerative disturbance in Bruch’s membrane-retinal pigment epithelium complex.3 The fragile blood vessels associated with choroidal neovascular membrane easily leak blood and/or fluid into the subretinal pigment epithelium, subretinal, or intraretinal space causing damage to the overlying retinal tissue and photoreceptors. The resultant damage to the photoreceptors and adjacent retinal tissue can result in stimulation of outer retinal tubulation formation as explained above.
Choroidal neovascular membranes are characterized into two different variants, which differ in pathophysiology, location in relation to the retinal pigment epithelium, and propensity to develop outer retinal tubulations. An occult choroidal neovascular membrane, or type I, typically forms below the retinal pigment epithelium and is ill-defined on fluorescein angiography. Indocyanine green angiography can aid in imaging occult membranes caused by fluorescein not leaking from healthy choroidal vessels and because of the retinal pigment epithelium blocking less of its emitted light. Type I neovascular membranes are more commonly associated with entities like AMD. A classic choroidal neovascular membrane, or type II, typically forms above the retinal pigmented epithelium, lying between the neurosensory retina and the retinal pigmented epithelium, with adjacent fluid leakage into the subretinal space. Type II neovascular membranes are more commonly linked to conditions like presumed ocular histoplasmosis syndrome and myopic degeneration, and AMD.
Although outer retinal tubulations have been documented in many conditions with both types of choroidal neovascular membranes, classic membranes have a higher predilection for outer retinal tubule formation.4 This association is likely caused by the subretinal location having direct contact with photoreceptors. The fact that the classic membranes are associated with fluid leakage at a level that directly affects the photoreceptors may contribute to worse baseline visual acuity, and greater overall vision loss, even in the presence of compensatory outer retinal tubule formation.4
Both types of neovascular membranes provide a mechanical alteration in the ellipsoid zone by physically pushing the photoreceptors in the direction of the inner retina at both the retinal pigment epithelium and subretinal levels, which could serve as a stimulus for outer retinal tubule formation because the photoreceptors would be in close proximity to one another. Our cases of wet AMD (case 1 and 2) show outer retinal tubule formation secondary to choroidal neovascular membrane formation that is located directly above the area of fibrosis with extensive retinal pigment epithelium disruption, perhaps supporting this concept (Figs. 1D and 2D). In the literature, it has been suggested that fluid leakage from the choroidal neovascular membrane and secondary ischemia can provide stimulation for outer retinal tubulation formation.4 Collaborative evidence would include the fact that chronicity of disease increases the incidence of tubular formation. Outer retinal tubulations are more commonly observed after a longstanding history of choroidal neovascularization.4
Another common cause of choroidal neovascular membrane is presumed ocular histoplasmosis syndrome. Presumed ocular histoplasmosis syndrome is a distinct chorioretinal disorder that is the result of a fungal infection endemic to river valleys. The pathophysiology of presumed ocular histoplasmosis syndrome involves disruptions in Bruch’s membrane created by blood-borne Histoplasma capsulatum. Focal infection or inflammation of the choroid adjacent to a break in Bruch’s membrane provides an opening through which pre-existing macular lesions reactivate and gain access into the subretinal space.3 Breaks in Bruch’s membrane and associated hypoxia, and inflammation, can also result in the development of choroidal neovascular membrane with subsequent tubule formation. In our case of ocular histoplasmosis (case 3), tubule development is noted adjacent to the area of disciform scarring and within an area of severe retinal and retinal pigment atrophy (Fig. 3D), suggesting the cause of tubules may be associated with either severe atrophy or secondary leakage and scarring linked to the old choroidal neovascular membrane.
Hereditary retinal-choroidal dystrophies have also been linked to outer retinal tubule formation including gyrate atrophy, choroideremia, cone dystrophy, Bietti crystalline dystrophy, Stargardt disease, and pattern dystrophy. Central areolar choroidal dystrophy is a macular dystrophy described as an ovoid, mottled depigmentation and atrophy of the posterior pole primarily affecting the choriocapillaris and retinal pigment epithelium.5 Central areolar choroidal dystrophy is a predominantly autosomal dominant disorder linked to a mutation in the Arg142Trp peripherin/RDS gene, but autosomal recessive and sporadic cases have been reported.5 The atrophic and degenerative changes to the retinal pigment epithelium caused by genetic-related photoreceptor apoptosis provide the precursor for eventual tubule formation. In our case of central areolar choroidal dystrophy (case 4), tubule formation may have occurred as a result of retinal pigment atrophy (Fig. 5C, D).
Pathological myopia is the second most common cause of choroidal neovascularization after AMD, accounting for 60% of all choroidal neovascular membranes in patients younger than 50.6 The pathophysiology of tubule formation in patients with pathological myopia may differ from those previously illustrated in cases of AMD and histoplasmosis. In these patients, outer retinal tubulations without choroidal neovascular membranes likely occur secondary to mechanical stress and retinal pigment epithelium/photoreceptor damage resulting from stretching and thinning of the choroid and retinal tissue. This degenerative process may cause remodeling of the outer retinal layers associated with outer retinal tubulation formation. Patients with pathological myopia that manifest choroidal neovascular membranes may also develop tubule formation with associated mechanical damage linked to a thinned retina and choroid or secondary outer retinal damage caused by fluid or blood leakage from choroidal neovascular membranes (as previously described in the above entities). In our case of pathological myopia (case 5), because of the large area of macular scarring in both eyes, we propose that tubule formation occurred secondary to choroidal neovascular membrane formation with subsequent scarring. It has been well documented that among the many fundus changes in myopic patients, peripapillary atrophy and lacquer cracks are especially important predisposing findings associated with membrane formation and, thus, may contribute to tubule formation.6 One study in particular found that lacquer cracks and patchy atrophy within one disc diameter of the fovea are important predisposing findings for choroidal neovascular membranes, noted in 29.4 and 20% of myopic neovascular membranes in the right and left eye, respectively.7
Outer retinal tubulation has been reported in a variety of retinal degenerations, dystrophies, and disease entities affecting the outer retina and retinal pigment epithelium. These include, but are not limited to, pattern dystrophy, acute zonal occult outer retinopathy, retinitis pigmentosa, Stargardt’s disease, gyrate atrophy, and choroideremia.2,8 Although the pathogenesis of each entity varies, they share the commonality of disruption, disorganization, and alteration of the photoreceptors, outer retina, and retinal pigment epithelium.
Outer retinal tubulation represents an inactivate process and therefore does not require treatment when discovered in isolation. Thus, it is important to distinguish such entities from other more frequently encountered conditions, which may mimic the appearance of tubular formation and may require further treatment. Such conditions include cystoid macular edema (Fig. 6). Several key characteristics can differentiate tubule formation from macular edema including location in the retina, shape of the lesion, and characteristics seen on OCT. Tubules are localized to the outer nuclear layer and have an oval well-delineated circular appearance on OCT. Cystoid macular edema is commonly localized in the inner retina or at the junction of inner and outer retina, specifically at or above the outer plexiform layer. Contrary to the oval shape of retinal tubules, macular edema tends to be associated with petalloid round shape spaces in the OCT.2 The reflectivity pattern on OCT can also help to distinguish between the two entities, as tubules tend to have a hyperreflective ring surrounding the hyporeflective lesion, whereas true macular edema does not (Fig. 7).2,4 It has been proposed that the hyperreflective ring seen in outer retinal tubules represents malformed photoreceptor outer segments.2 These lesions are quite small in size, ranging from 40 to 140 μm and can easily be overlooked.1 Therefore, practitioners should dynamically view the retinal cross-sections on OCT and use raster lines for higher resolution.
As previously stated, it is theorized that outer retinal tubulations are stable retinal structures that represent disease chronicity. However, it has been suggested that tubules can respond to antivascular endothelial growth factor treatment because of the vascular component associated with the formation of retinal tubules. One study looked at the response of retinal tubules to antivascular endothelial growth factor injections and found that half of the tubules were stable over time and a few tubules collapsed during treatment and then reappeared after treatment was cessated.9 Further research is needed to evaluate the efficacy and/or necessity of treating outer retinal tubules with antivascular endothelial growth factor injections.
It is of clinical significance to distinguish outer retinal tubulation structures from other masqueraders such as cystoid macular edema, as the latter may warrant treatment. It is thought that the tubular structure represents a stable retinal finding rather than an ongoing active process, thus they do not require further management. Understanding how the presence of outer retinal tubulation can affect the prognosis of a particular condition may become useful when managing many chronic retinal conditions.
The five cases presented highlight the myriad of diseases associated with outer retinal tubulations. Although distinct in nature and etiology, the pathophysiology of each disease process involves damage to the retina at the level of the photoreceptors and/or retinal pigment epithelium. Outer retinal tubules tend to be present in more severe, end-stage disease and are usually associated with lower overall best-corrected visual acuity. By correctly differentiating tubules from other active disease findings, such as cystoid macular edema, unnecessary referrals and interventions can be minimized. Understanding the various disease entities associated with outer retinal tubules could give further insight into the mechanism of tubular formation.
Nova Southeastern University
College of Optometry
3200 South University Dr
Ft. Lauderdale, FL 33328-2018
Received April 26, 2016; accepted January 11, 2017.
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Keywords:© 2017 American Academy of Optometry
outer retinal tabulation; retinal pigment epithelium; age-related macular degeneration; central areolar choroidal dystrophy; cystoid macular edema