Ultra-high resolution optical coherence tomography (OCT) systems can generate superb atlas-grade images that readily highlight macular pathology. However, instead of reviewing atlas-grade images, clinicians must become comfortable with rapidly and accurately interpreting “real world” OCT images in busy clinic settings, with typical limitations involving system capabilities, operator skill, ocular media clarity and patient cooperation.

This real-world OCT case series, derived from a typical retina clinic setting, demonstrates common but subtle findings that carry prognostic significance and/or impact management. This case series is organized by anatomic location of findings, from inner retina to outer retina.

Specifically, this series reviews OCT findings commonly mistaken for cystoid macular edema, OCT depictions of ellipsoid zone disruptions correlating with symptomatic functional vision loss, and OCT demonstrations of the variations in retinal pigment epithelial (RPE) elevations that carry diagnostic, prognostic and therapeutic implications.

1. OCT FINDINGS COMMONLY MISTAKEN FOR CYSTOID MACULAR EDEMA

Not all hyporeflective intraretinal spaces convey an active exudative process requiring treatment.

Pseudo-cysts in macular telangiectasia type 2

A 75-year-old female presented with a progressive blurring of central vision bilaterally. She had a 15-year history of diabetes but never required treatment for diabetic retinopathy. Her visual acuity (VA) measured 20/50 bilaterally and moderate cataracts were noted in both eyes (BE). Fluorescein angiography (FA) revealed staining temporal to the foveal avascular zone in both eyes (Figure 1A) in the location of fine telangiectatic capillaries and dilated venules (Figure 1B). Macular OCT identified pseudocysts without significant neurosensory thickening BE and some ellipsoid zone disruption in the right eye (RE) (Figure 1C). Observation was recommended.

Differentiating pseudocysts from cystoid macular edema (CME) of other etiologies has important clinical implications as antivascular endothelial growth factor (anti-VEGF) therapy is not convincingly effective in treating macular telangiectasia type 2 and may unnecessarily expose patients to risks of intravitreal injection.¹ Type 2 macular telangiectasia is a rare, degenerative bilateral condition that typically presents in the fifth to sixth decade of life with the variable findings of reduced retinal transparency, crystalline deposits, mildly ectatic capillaries and blunted, slightly dilated venules. As disease advances, atrophy can develop as well as lamellar or full thickness holes and neovascularization.

Macular OCT classically reveals pseudocysts, which are atrophic hyporeflective spaces that do not show neurosensory thickening and are not associated with angiographic leakage or pooling of fluorescein dye. These pseudocysts are likely due to retinal degeneration and are pathophysiologically analogous to spaces in X-linked retinoschisis.¹ Other macular OCT findings include ellipsoid zone disruption, and in advanced disease, atrophy of the neurosensory retina and sequelae from neovascularization.

Outer retinal tubulation in neovascular AMD

An 87-year-old male presented with a several-year history of progressive bilateral metamorphopsia and scotoma. He had been treated with numerous anti-VEGF injections in his RE. VA measured 20/70 RE and 20/400 left eye (LE), and fundus examination revealed bilateral advanced geographic atrophy (GA), drusen and pigment clumping (Figure 2A). Macular OCT demonstrated outer retinal tubulation RE (red arrow, Figure 2B) as well as bilateral RPE atrophy with increased signal penetration into the choroid (blue arrows, Figure 2B).

Incidentally, the nerve fiber layer of the maculopapillary bundle is denoted by the yellow arrow (yellow arrow, Figure 2B). Due to disease inactivity, observation was recommended with close follow-up.

Differentiating outer retinal tubulation (ORT) from solitary cystoid spaces secondary to neovascular age-related macular degeneration (AMD) is important as ORT is not an indication to treat with anti-VEGF therapy. ORT is an OCT finding characterized by a hyporeflective cavity surrounded by a hyper-reflective wall and is found in the outer nuclear layer.

Histologically, this correlates with a sphere of surviving cones surrounded by Muller cell processes; the finding portends worse visual acuity outcomes.^2,3 Most commonly found in advanced AMD, ORT can also be found in hereditary retinal degenerations.

Geographic atrophy, which was also noted in this case, is recognized as discrete areas of increased signal penetration into the choroid, and is a common finding in both non-neovascular AMD and neovascular AMD. Laser photocoagulation scars, which atrophy over time, can also yield multiple discrete areas of increased signal penetration into the choroid.

2. ELLIPSOID ZONE DISRUPTIONS CORRELATING WITH SYMPTOMATIC FUNCTIONAL VISION LOSS

The ellipsoid zone represents the regularly oriented, inner portion of the photoreceptor layer that is densely packed with mitochondria, and has unique, clinically useful functional significance.

Parafoveal ellipsoid zone loss from hydroxychloroquine retinopathy

A 65-year-old female presented with a two-month history of bilateral central vision loss. VA measured 20/30 RE and 20/20 LE. She endorsed a 20-year history of hydroxychloroquine use that was stopped several years prior to presentation. Fundus examination revealed a bilateral bull’s eye pattern of RPE changes (Figure 3A) while fundus autofluorescence (FAF) demonstrated a bilateral ring of hypoautofluorescence surrounded by a ring of hyperautofluorescence (Figure 3B). Macular OCT identified parafoveal ellipsoid zone loss (leaving the central ellipsoid zone intact, reminiscent of a “flying saucer” and hence the “flying saucer sign”) along with generalized retinal thinning (Figure 3C, red arrows depicting the edge of intact foveolar ellipsoid zone). Even though she had not taken hydroxychloroquine for a number of years, this patient demonstrated progression of hydroxychloroquine toxicity.

Macular OCT should be included among the tests for hydroxychloroquine (Plaquenil, Sanofi-Synthelabo, Inc.) maculopathy, as it can reveal disruption of the parafoveal ellipsoid zone (which can correlate with paracentral vision loss), as well as a loss of the external limiting membrane, parafoveal thinning of the outer nuclear layer, and RPE atrophy.⁴ Hydroxychloroquine is used for a number of rheumatologic disorders. The risk of toxicity is very low in patients who consume less than 5.0 mg/kg of real body weight and who have been on therapy for less than 10 years.⁵ Early in the course of the disease, fundus appearance is normal and in later stages a bull’s eye maculopathy develops. Other tests that can help identify early pathology include a multifocal electroretinography (ERG), 10-2 Humphrey visual field testing and FAF. Early identification of pathologic changes is crucial because this progressive retinopathy is irreversible and patients should stop therapy.

Subtle ellipsoid zone disruption with subsequent improvement after laser pointer injury

A 13-year-old male presented with a one-month history of an RE central scotoma following a laser injury. VA measured 20/20 bilaterally, and fundus and red-free macular evaluation were grossly normal (Figure 4A). His symptoms were difficult to explain until macular OCT revealed a subtle disruption of the foveal ellipsoid zone RE (Red arrows, Figure 4B), correlating to his functional complaints. The patient was observed without treatment and had a slow resolution of the scotoma over the ensuing six weeks with partial resolution of the ellipsoid zone irregularity (Figure 4C).

Ellipsoid zone disruption correlates with symptomatic functional vision loss and, in some disorders, can improve over time, correlating with improving symptoms. Laser retinal injuries have become more common with the widespread availability of inexpensive and high-energy, handheld laser pointers. Important variables in determining the degree of ophthalmic injury include the amount of energy delivered, the duration of exposure and the location of retinal involvement.⁶ Fundus examination can be normal with mild injury, and in more severe cases yellowing or whitening of the retina or a macular hole can develop. Macular OCT changes range from subtle disruption of the ellipsoid zone and inner retinal hyper-reflectivity to subretinal hemorrhage and macular hole formation in severe cases. Steroid treatment for laser retinal injury has been advocated by some authors, but the efficacy in humans and in preclinical models remains controversial.⁷

Ellipsoid and interdigitation zone atrophy from solar maculopathy

A 52-year-old schizophrenic male presented with a one-year history of bilateral, central, progressive scotomas after prolonged periods of staring at the sun. VA measured 20/20 RE and 20/30 LE and fundus examination revealed bilateral foveal atrophy with pigment clumping (Figure 5A). FA demonstrated central hypofluorescence with surrounding staining (Figure 5B) and macular OCT identified foveolar ellipsoid zone and interdigitation zone atrophy (Figure 5C; ELM [External limiting membrane], EZ [Ellipsoid zone], IDZ [Interdigitation zone], RPE [Retinal pigment epithelium]), accounting for his symptoms. Note that the external limiting membrane and RPE remain intact centrally.

Macular OCT is a sensitive test in identifying outer neurosensory retinal abnormalities, such as ellipsoid zone disruption, as well as RPE atrophy.⁸ A history of prolonged sun gazing can often be difficult to elicit from patients with an underlying psychiatric condition and the degree of pathology is primarily determined by the duration of exposure.⁹ Early fundus changes include areas of yellow pigmentation surrounded by a faint gray irregularity, which then progresses to reddish lesions, and eventually neurosensory retinal and RPE atrophy with scar formation.^8-10

3. VARIATIONS OF RPE ELEVATIONS WITH DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC IMPLICATIONS

In addition to the most commonly encountered serous and fibrovascular PEDs in AMD, RPE elevations have numerous variations, which carry differing diagnostic, prognostic and therapeutic implications.

Retinal pigment epithelial tear in neovascular AMD

An 85-year-old female presented with a six-month history of a central blur in her RE, for which she had previously received numerous anti-VEGF injections for neovascular AMD. VA measured 20/200 RE and 20/60 LE, and fundus examination revealed a moderate RPE tear in her RE along with bilateral drusen and RPE changes. FA demonstrated a large window defect in the exposed area of the RPE tear along with an area of hypofluorescence from blockage by the heaped-up RPE in her RE, and bilateral staining consistent with drusen and RPE changes (Figure 6A). Macular OCT revealed an irregularly elevated and corrugated area of RPE (Figure 6B) adjacent to a denuded area of atrophy RE with increased signal penetration into the choroid (Figure 6B), along with bilateral drusen and a small area of cystoid macular edema LE (Figure 6B). Anti-VEGF therapy was continued in the RE and the patient was monitored closely.

RPE tears are a complication of pigment epithelial detachments (PED) and can occur spontaneously or be precipitated by anti-VEGF therapy. They are associated with a poor visual prognosis when the fovea is involved. Fundus examination reveals an area of bare choroid adjacent to retracted RPE, which is best delineated with fundus autofluorescence. Macular OCT shows a disruption of the RPE layer with adjacent increased signal penetration into the choroid; the elevated RPE is irregular, corrugated and hyper-reflective overlying a hyporeflective shadow. The differential diagnosis for RPE tears include GA due to advanced AMD and various etiologies of PED; the history and corrugated appearance of RPE on OCT can differentiate these pathologies. Anti-VEGF therapy should be continued in these patients despite the possibility that the therapy initially precipitated the tear, until the disappearance of underlying evidence of active choroidal neovascularization (CNV).¹¹

Polyp in polypoidal choroidal vasculopathy

An 89-year-old African-American female presented with a two-week history of central blurring in her RE, and VA measured 20/40 RE and 20/25 LE. Posterior pole evaluation revealed a hemorrhagic PED and suggested a polyp temporal to the optic disc in the RE, with a normal left posterior pole (Figure 7A). Macular OCT demonstrated a large area of subretinal fluid as well as a likely polyp with steeply elevated contours (White arrow, Figure 7B). Monthly anti-VEGF therapy was initiated and the patient experienced an improvement in visual acuity and anatomic resolution of exudation.

Macular OCT can frequently identify polyps and other findings of polypoidal choroidal vasculopathy (PCV), such as dilated choroidal vessels. Identifying polyps in PCV and differentiating them from other forms of choroidal neovascularization has clinical implications, as the EVEREST trial found that combination therapy (photodynamic therapy with VEGF blockade) was superior to anti-VEGF therapy alone.¹² PCV is a variation of AMD characterized by polypoidal lesions resulting in serous and serosanguineous detachments of the neurosensory retina and RPE. Polyps can sometimes be seen on posterior pole examination, but are best identified with indocyanine green angiography. En face macular OCT can identify polyp networks and also reveal the “hematocrit sign”, in which blood settles into serous and red blood cell components.¹³ A sharp PED peak (as in this case), a PED notch and a hyporeflective PED lumen within a hyper-reflective lesion adherent to the outer surface of the RPE are characteristics that can help differentiate PCV from serous PEDs.¹⁴

Adult-onset foveomacular vitelliform dystrophy

An 85-year-old, glaucomatous female presented with a one-month history of bilateral central blurring. Her VA measured 20/200 RE (chronically poor) and 20/30 LE and she had a history of severe glaucoma in her RE necessitating tube shunt placement. Fundus examination identified symmetric yellow foveal lesions with pigment clumping (Figure 8A) and FA demonstrated an early bilateral blocking defect without staining or leakage (Figure 8B). Red-free photographs provided greater contrast of the lesions (Figure 8C) and macular OCT identified bilateral hyper-reflective subretinal material underlying a mottled ellipsoid zone in the LE (Figure 8D).

Differentiating adult-onset foveomacular vitelliform dystrophy (AOFVD) from PEDs of neovascular AMD is important because these lesions are typically indolent and only require treatment if secondary neovascularization develops in chronic cases. AOFVD typically presents with mild visual disturbances between the ages of 30 and 50.¹⁵ The natural history of a classical AOFVD lesion is the development of an “egg-yolk” spot with subsequent degradation leading to a pseudohypopyon and eventually an area of atrophic neurosensory retina and RPE.15 Macular OCT identifies a dome-shaped, hyper-reflective subretinal mass with overlying ellipsoid-zone mottling during the vitelliform stage, and progressive degradation of the hyper-reflective material as the lesion involutes.¹⁵_,¹⁶ The disease can also be differentiated from Best disease by a normal electro-oculogram (EOG) along with a nonpediatric or young-adult onset.

CONCLUSION

This case series is limited in that space constraints precluded a comprehensive review of the rich variation in OCT findings, particularly in infectious, inflammatory and neoplastic disorders. Still, this real-world OCT case series, derived from a typical retina clinic setting with its inherent limitations, demonstrates common but subtle findings that can impact management. Major themes include findings commonly mistaken for CME not requiring treatment, ellipsoid zone disruptions correlating with symptomatic functional vision loss, and variations of RPE elevations with diagnostic, prognostic and therapeutic implications.

In the future, with rising clinic volumes, new imaging technologies such as OCT angiography and complex in-office treatments, rapid and accurate interpretation of real-world imaging will be increasingly important. OM

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About the Authors

Peter Bracha, MD, is a resident and Thomas A. Ciulla, MD, MBA, is a volunteer clinical professor of Ophthalmology at Indiana University School of Medicine. Dr. Ciulla is on the Board of Directors of Midwest Eye Institute, an ophthalmic subspecialty tertiary center. He can be reached via e-mail at thomasciulla@gmail.com.

Neither author reports any financial interests in products mentioned in this article.