A retrospective case analysis of high-risk biomarkers for geographic atrophy development and multimodal imaging features of early GA

Image Credit: AdobeStock/ОлександрЛуценко

Age-related macular degeneration (AMD) accounts for significant visual morbidity.^1,2 Geographic atrophy, an advanced, progressive manifestation of AMD, is associated with significant reduction in vision-related quality of life, negatively impacts activities of daily living, and has a many psychological impacts.² GA impacts approximately 1 million individuals in the United States, accounting for approximately 20% of AMD cases.^3,4 Expansion of GA is irreversible, and the median time from non-central to central involvement is 2.5 years.⁵

While effective treatments for neovascular, exudative AMD have been available for many years, the management of GA has been largely limited to observation.⁶ More recently however, the reduction of GA progression seen with intravitreal complement inhibition therapies has potential to improve outcomes and delay central involvement, particularly with early detection and treatment.⁶ As these therapies only slow progression, it is critical to detect high-risk biomarkers and warning signs of incipient GA to identify those patients who will most likely progress and thus benefit from close follow-up and early referral once GA develops.^6,7

Using high-resolution optical coherence tomography (OCT) eye care providers can identify early stages of AMD-related atrophy prior to clinical detection.^6,8 Several OCT biomarkers have been identified which predict increased risk of conversion to GA.^6,8 The Classification of Atrophy Meeting defined OCT-based terminology for AMD-related atrophy including complete retinal pigment epithelium and outer retinal atrophy (cRORA) and incomplete retinal pigment epithelium and outer retinal atrophy (iRORA).^8,9 Nascent GA, represented by iRORA, is broadly defined as non-uniform choroidal hypertransmission, retinal pigment epithelium (RPE) attenuation, and photoreceptor disruption (Figure 1).^9,10 The latter may include hyporeflective wedges within the Henle fiber layer, subsidence of the inner nuclear and outer plexiform layers, thinning of the outer nuclear layer or discontinuity of the ellipsoid zone.^9,11 End-stage atrophic processes, cRORA or GA, are characterized by homogenous choroidal hypertransmission underlying RPE and photoreceptor loss with a diameter of at least 250µm (Figure 1).⁸

Figure 1. Cross-sectional optical coherence tomography features of geographic atrophy in a 62-year-old female with age-related macular degeneration. iRORA: Incomplete RPE and outer retinal atrophy: variable hypertransmission with intermittent disruption of ellipsoid zone. Note the hyperreflective intraretinal foci within the area of iRORA (blue arrowhead) and the adjacent outer plexiform and inner nuclear layer subsidence (red arrowhead) and hyporeflective wedge; cRORA: Complete RPE and outer retinal atrophy: homogenous choroidal hypertransmission (green arrowheads) and overlying RPE and photoreceptor loss. RPE: Retinal pigment epithelium. (Figures courtesy of Ethan Wohlgemuth, OD)

This case presents the retrospective analysis of an older male patient who presented to the optometry clinic with bilateral, multifocal, non-central cRORA which had developed and progressed over the course of 4 years. High risk biomarkers predictive of the development of GA will be discussed and applied to this case.

Case presentation

A 73-year-old Indigenous male presented for a follow-up appointment for AMD without visual complaints. He reported poor adherence with Amsler grid use and was not currently taking Age-Related Eye Disease Studies (AREDS) type supplements. He was a non-smoker. Pertinent ocular history included AMD and bilateral cataract surgery 5 years ago. Medical history included hypertension, dyslipidemia, coronary artery disease, and sinus bradycardia. Current medications included aspirin 81mg, atorvastatin 80mg, clopidogrel 75mg, lisinopril 10mg, and nitroglycerin 0.4mg.

The patient first presented to the optometry clinic 4 years ago, at which time baseline imaging was obtained. At baseline, color fundus photography demonstrated extensive confluent soft drusen with several refractile areas in both eyes. In the right eye, these refractile areas corresponded to hyperreflective crystalline deposits on OCT. In the left eye, one refractile area corresponded to a hyporeflective drusen core and another to a hyperreflective crystalline deposit. Hyperpigmentary changes corresponding to intraretinal hyperreflective foci on OCT were also noted in the left eye. An area of iRORA was appreciated on OCT of the left eye and corresponded to a small, round area of increased choroidal visibility on color fundus photography. Subretinal drusenoid deposits were noted on OCT throughout both eyes. At this appointment, the patient was diagnosed with intermediate-stage AMD in both eyes per the Beckman AMD classification scheme.¹²

Figure 2. Optical coherence tomography biomarkers and features of geographic atrophy in the right eye showing progression over 4 years. Color fundus photo insets show OCT B-scan location (white line). Baseline: A, B, C. 2-year follow-up: D, E, F. 4-year follow-up: G, H, I. Left
column: Hyperreflective crystalline deposit (pink arrowhead) progresses to cRORA within 4 years. cRORA is denoted by outer plexiform and inner nuclear layer subsidence (red arrowhead) and choroidal hypertransmission (green arrowheads). An adjacent area of photoreceptor disruption with underlying variable choroidal hypertransmission (teal arrowhead) developed nasally at the margin of another area of cRORA (not shown). Middle column: A hyperreflective crystalline deposit (pink arrowhead) progresses to cRORA within 4 years. Subsidence of the inner nuclear and outer plexiform layers (red arrowhead) and homogenous choroidal hypertransmission (green arrowheads) is appreciated at the site of cRORA. At the 2-year follow-up adjacent subretinal drusenoid deposits can be appreciated
(orange arrowhead). Right column: Large, soft drusen are seen at baseline with adjacent subretinal drusenoid deposits (orange arrowheads). At the 2-year follow-up, there is relative photoreceptor disruption overlying the drusen with underlying variable choroidal
hypertransmission (teal arrowheads) suggestive of incipient iRORA. At the 4 year-follow-up cRORA has developed with outer plexiform and inner nuclear layer subsidence (red arrowhead) and choroidal hypertransmission (green arrowheads). Adjacent subretinal drusenoid deposits (orange arrowheads) are seen temporally. cRORA: Complete RPE and outer retinal atrophy; iRORA: Incomplete RPE and outer retinal atrophy; RPE: retinal pigment epithelium (Figures courtesy of Ethan Wohlgemuth, OD)

Retrospective analysis of the right eye over 4 years of follow-up with serial OCT demonstrated cRORA development in the superior-temporal perifovea and inferior parafovea (Figure 2). These corresponded to sites of hyperreflective crystalline deposits at baseline. Additionally, a large soft druse located in the inferior nasal perifovea at baseline developed underlying choroidal hypertransmission columns suggestive of early photoreceptor and RPE disruption at the 2-year follow-up. This druse subsequently collapsed and converted to cRORA.

Figure 3. Optical coherence tomography biomarkers and features of geographic atrophy in the left eye showing progression over 4 years. Color fundus photo insets show OCT B-scan location (white line). Baseline: A, B, C. 2-year follow-up: D, E, F. 4-year follow-up: G, H, I. Left column: A hyporeflective drusen core (yellow arrowhead) develops iRORA within 4 years, represented by RPE and photoreceptor disruption and underlying choroidal hypertransmission (teal arrowhead). At the 2-year follow-up, a subretinal drusenoid deposit (orange arrowhead) is noted adjacent to the druse. Middle column: A large soft druse with an
overlying intraretinal hyperreflective foci (blue arrowhead) develops cRORA within 4 years. At baseline, an adjacent hyperreflective crystalline deposit (pink arrowhead) is noted, an overlying intraretinal hyperreflective foci is noted at the 2-year follow-up and this area
develops cRORA at 4 years. Subsidence of the inner nuclear and outer plexiform layers and homogenous choroidal hypertransmission (green arrowheads) is appreciated at the sites of cRORA. An adjacent area of iRORA develops nasally with subsidence of the outer plexiform and inner nuclear layers (red arrowhead), hyporeflective wedges and choroidal
hypertransmission at the 4-year follow-up. Right column: An area of iRORA at baseline denoted by outer plexiform and inner nuclear layer subsidence (red arrowhead) converts to cRORA within 2 years with homogenous choroidal hypertransmission (green arrowheads). At
the 2-year follow-up an adjacent hyperreflective crystalline deposit (pink arrowhead) is noted nasally which progresses to iRORA by the 4-year follow-up with subsidence of the outer plexiform and inner nuclear layers (red arrowhead), a hyporeflective wedge and variable choroidal hypertransmission. cRORA: Complete RPE and outer retinal atrophy. iRORA: Incomplete RPE and outer retinal atrophy; RPE: retinal pigment epithelium (Figures courtesy of Ethan Wohlgemuth, OD)

Retrospective analysis of the left eye over 4 years of follow-up with serial OCT demonstrated cRORA development in the nasal and temporal parafovea, both of which demonstrated hyperpigmentation on color fundus photography and intraretinal hyperreflective foci on OCT prior to conversion to cRORA (Figure 3). The area of iRORA at baseline converted to cRORA within 1 year, and subsequently expanded with further follow-up. Three areas of incipient iRORA had developed at the final follow-up, one corresponding topographically to an earlier hyporeflective drusen core and another to a hyperreflective crystalline deposit.

At the current appointment, 4-years after initial presentation, best-corrected visual acuity was 20/20 in the right eye and 20/25 in the left eye; there was no improvement with pinhole in the left eye. Confrontation visual fields, extraocular motilities, pupil testing and anterior segment examination were unremarkable.

Figure 4. Color fundus photography showing development and progression of geographic atrophy (GA) in the right and left eyes over 4 years. A & E: Baseline. B & F: 2-year follow-up. C & G: 4-year follow-up. D & H: Fundus autofluorescence imaging (FAF) at the 4-year follow-up. Top row: Right eye: Baseline color fundus photography demonstrates extensive confluent soft drusen with several refractile areas (A, pink arrowheads). Sequential follow-up demonstrates regression and collapse of drusen with the development of several areas of extrafoveal GA (C, green arrowheads). FAF imaging at the 4-year follow-up demonstrates hypo-autofluorescence corresponding to areas of GA (D, red arrowheads), and a ring of perifoveal hyper-fluorescence (D, red arrow). Bottom row: Left eye: Baseline color fundus photography demonstrates extensive confluent soft drusen relatively sparing the inferior temporal
perifovea. Hyperpigmentation is appreciated in the superior nasal parafovea (E, blue arrowhead). An area of increased choroidal visibility (E, teal arrowhead) is noted in the inferior temporal parafovea. Sequential follow-up demonstrates collapse and regression of drusen and the development of extrafoveal GA (F & G, green arrowheads). FAF imaging at the 4-year follow-up demonstrates hypo-autofluorescence corresponding to areas of GA (H, red arrowheads). Speckled areas of hyper-autofluorescence are appreciated throughout the perifoveal area and at the margin of GA. (Figures courtesy of Ethan Wohlgemuth, OD)

Dilated posterior segment examination was remarkable for multifocal, non-central GA both eyes (Figure 4). There was perifoveal drusen in both eyes. While there was no foveal involvement of GA, both eyes demonstrated regions of GA within close proximity to the fovea. Posterior segment examination was otherwise unremarkable.

Ancillary ophthalmic imaging included color fundus photography, fundus autofluorescence imaging (FAF), OCT and OCT-Angiography. FAF imaging revealed multiple, well-demarcated, extrafoveal regions of hypo-autofluorescence. There was a ring of speckled, perifoveal hyper-autofluorescence in the right eye. In the left eye, speckled hyper-autofluorescence was appreciated throughout the perifoveal area and at the margin of GA lesions. There were 4 areas of cRORA on OCT in the right eye and 3 areas of cRORA in the left eye. An additional 3 areas of iRORA were noted in the left eye. These corresponded to areas of relative hypo-autofluorescence on FAF (Figure 4). There was no subfoveal ellipsoid zone disruption and no evidence of choroidal neovascularization.

The patient was diagnosed with late, non-neovascular age-related macular degeneration with multifocal, extrafoveal cRORA in both eyes according to the Beckman AMD classification scheme.¹² He was educated regarding progressive GA from macular degeneration and management options including complement inhibition therapies were discussed; however, the patient declined referral for such treatment. The patient was provided with an Amsler grid for at-home vision monitoring and was advised to initiate vitamin supplementation with an AREDS2 formulation.¹³ Follow-up was arranged in 4 months.

Discussion

Several OCT biomarkers have been identified which predict increased risk of conversion to GA.^6-8 These include high central drusen volume, intraretinal hyperreflective foci (IHRF), subretinal drusenoid deposits (SDD), hyporeflective drusen cores, hyperreflective crystalline deposits, and a thin double layer sign.^6-8,11,14 With the exception of a thin double layer sign, these biomarkers can be appreciated in the above case, and were associated topographically with future areas of cRORA development.

Literature suggests that the mean time for incipient iRORA to convert to cRORA is approximately 15 months, and over 90% of eyes will develop cRORA within 2 years of iRORA detection.¹⁴ In the above case, the area of iRORA present at baseline in the left eye converted to cRORA within 1 year. Similarly, an area of iRORA which was noted in the right eye at the 2-year follow-up had converted to cRORA 2 years later at the final follow-up.

Figure 5. Trend-based analysis of geographic atrophy progression in the right eye over 4 years. Top row: Serial near-infrared reflectance imaging (NIR). Development of GA represented by round hyperreflective lesions (green arrowheads) is noted at the 4-year follow-up; middle row: serial cross-sectional optical coherence tomography through the fovea. A decrease in drusen volume can be appreciated from baseline to the 4-year follow-up; bottom row: Cirrus Advanced RPE trend analysis (Carl Zeiss Meditec, Inc., Dublin, CA, USA). Orange line: RPE elevation volume (correlate of drusen volume) within the central 3mm. Green line: sub-RPE illumination area (correlate of cRORA choroidal hypertransmission area) within the central 5mm. RPE: Retinal pigment epithelium. cRORA: complete RPE and outer retina atrophy. Drusen volume at baseline was high, 0.035mm³. With sequential follow- up, central drusen volume decreased as the area of cRORA increased.

High central drusen volume has been associated with increased risk of development of GA.^7,15,16 Specifically, high central drusen volume refers to drusen volume greater or equal to 0.03mm³ within the central 3mm.⁷ Abdelfattah et al. reported a four-fold increased risk of developing GA in patients with high central drusen volume.¹⁵ While some OCT software systems may automatically calculate drusen volume, clinicians can accurately differentiate high and low central drusen volume through qualitative review of OCT B-scans.¹⁷ Drusen volume, however, is dynamic and may decline as drusen collapse and GA develops.^7,15,18 In the above case, qualitative assessment suggested high central drusen volume at baseline, and the Cirrus Advanced RPE Analysis software (Carl Zeiss Meditec, Inc., Dublin, CA, USA) indicated central drusen volume of 0.035mm³ in the right eye (Figure 5), and 0.02mm³ in the left eye (Figure 6). Central drusen volume in the left eye subsequently increased to 0.03mm³ within 1 year. As the patient was monitored over the following 4 years, central drusen volume decreased dramatically in both eyes as atrophy developed, showcasing the collapse and regression of drusen which precedes the development of GA.¹⁰ At the final follow-up, central drusen volume was 0.01mm³ in the right eye and negligible in the left eye.

Figure 6. Trend-based analysis of geographic atrophy progression in the left eye over 4 years. Top row: Serial near-infrared reflectance imaging (NIR). Development of GA represented by round hyperreflective lesions (green arrowheads) is noted at the 4-year follow-up. An irregular highly reflective lesion (pink arrow) is appreciated at the 2-year follow-up which is correlated with a hyperreflective crystalline deposit on optical coherence tomography. At the 4-year follow-up, this area develops GA; Middle row: serial cross-sectional optical coherence tomography through the fovea. Bottom row: Cirrus Advanced RPE trend analysis (Carl Zeiss
Meditec, Inc., Dublin, CA, USA). Orange line: RPE elevation volume (correlate of drusen volume) within the central 3mm. Green line: sub-RPE illumination area (correlate of cRORA choroidal hypertransmission area) within central 5mm. RPE: Retinal pigment epithelium. cRORA: complete RPE and outer retina atrophy. Drusen volume at baseline was moderate,
0.02mm³. Central drusen volume increased to 0.03mm3 at the 1-year follow-up and subsequently decreased as the area of cRORA increased.

The presence of IHRF is potentially the strongest OCT-biomarker for the development of cRORA.^7,16,19,20 The risk of cRORA associated with IHRF is dose-dependent, with greater quantity of IHRF suggesting higher risk of cRORA development.¹⁹ IHRF appear as discrete, hyperreflective, punctate lesions within the neurosensory retina on OCT and have equal reflectivity to the RPE layer.^11,14 These lesions typically correlate with hyperpigmentation on funduscopy, and have been proposed to represent anterior migration of abnormal RPE cells undergoing epithelial-to-mesenchymal transition.^19,21,22 In the above case, there was an IHRF overlying a large soft druse in the left eye at baseline. At the 4-year follow-up, this area had developed cRORA. A second IHRF was noted on OCT at the 2-year follow-up overlying a hyperreflective crystalline deposit, which subsequently converted to cRORA within 2 years.

Subretinal drusenoid deposits, also referred to as reticular pseudodrusen, are located anterior to the RPE at the level of the ellipsoid zone, whereas classic drusen are located posterior the RPE.^23-25 In a histological study of a patient with AMD who underwent exenteration, Greferath at al. reported that subretinal drusenoid deposits were associated with increased markers of retinal stress, localized photoreceptor disruption, and irregular RPE cell morphology.²⁴ Subretinal drusenoid deposits have also been associated with decreased choroidal vascular activity which may predispose to greater RPE dysfunction and development of advanced AMD.²⁶ Several studies have identified the presence of subretinal drusenoid deposits as a significant risk factor for conversion to cRORA.^7,20,27 While subretinal drusenoid deposits were appreciated at multiple locations in both eyes, they were not associated topographically with future cRORA development in this case. Similarly, Manafi et al. and Pasricha et al. reported that while subretinal drusenoid deposits suggested increased risk of conversion to GA at an eye level, this often occurred at locations without earlier subretinal drusenoid deposits.^18,20

Calcified drusen appear as white, refractile lesions on funduscopy and correspond to hyporeflective drusen cores on OCT imaging.^11,23 These lesions have also been referred to as refractile drusen and drusen with heterogeneous internal reflectivity.^11,23 Using near-infrared reflectance imaging, calcified drusen appear as brightly reflective areas.²³ The presence of hyporeflective drusen cores has been associated with increased risk of conversion to cRORA.^7,16,28-30 In this case, a hyporeflective drusen core was noted at baseline in the left eye. At the 2-year follow-up a subretinal drusenoid deposit was noted immediately adjacent to this lesion, and at the final follow-up there was incipient iRORA with early ellipsoid zone disruption and a focal underlying area of choroidal hypertransmission. The presence of iRORA at this location strongly suggests future risk of conversion to cRORA.³¹

Hyperreflective crystalline deposits, previously referred to as sub-RPE plaques, appear as hyperreflective, linear lesions located within the sub-RPE and basal lamina space on OCT.^11,32 They are yellow to hypopigmented on funduscopy and correspond with hyperreflective lesions on near-infrared reflectance.^11,32 Calcified drusen and hyperreflective crystalline deposits may appear similar on fundus examination, but are readily differentiated through review of OCT B-scans.³² Histological analysis suggests that hyperreflective crystalline deposits represent sub-RPE cholesterol crystals and avascular fibrosis.³² The presence of hyperreflective crystalline deposits suggests increased risk of cRORA development.³² In the above case, hyperreflective crystalline deposits were appreciated in both eyes at baseline, and these areas developed cRORA by the 4-year follow-up. A newly detected hyperreflective crystalline deposit was noted at the 2-year follow-up in the left eye, and iRORA developed 2 years later at this location.

Conclusion

Early detection of incipient GA is critical to determine which patients will most likely progress and thus benefit from close follow-up and future referral for consideration of complement inhibition treatment. Since these therapies only slow irreversible GA expansion, early treatment may provide the best opportunity to maintain visual function for as long as possible. As was seen in this case, high risk biomarkers such as high central drusen volume, intraretinal hyperreflective foci, subretinal drusenoid deposits, hyporeflective drusen cores, and hyperreflective crystalline deposits suggest increased risk of conversion to cRORA. Close follow-up is warranted for patients presenting with these features to allow for early detection of de novo GA development.

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