OPTICAL COHERENCE TOMOGRAPHY DIFFERENCE MAPS AND AVERAGE MACULAR VOLUME FOR GEOGRAPHIC ATROPHY Josh Wallsh, BS, Ron Gallemore, MD, PhD
Purpose: To demonstrate the ability to monitor geographic atrophy (GA) volumetrically through all retinal layers with high-resolution optical coherence tomography difference maps and average macular volume. Methods: Observational case report. Results: Two patients diagnosed with GA were followed up for multiple years with consecutive high-resolution optical coherence tomography studies along with fundus photography and fluorescein angiography or fundus autofluorescence. Difference maps visually reflect macular thinning associated with expansion of GA witnessed on alternative studies. In addition, these maps show progressive macular thinning within previously delineated areas of GA. Average macular volume quantitatively demonstrates the decreasing volume associated with the expanding atrophy. Conclusion: Difference maps and average macular volume allow quantitative analysis of GA and may be a useful tool for patient care and clinical trials. RETINAL CASES & BRIEF REPORTS 9:88–91, 2015
From the Retina Macula Institute, Torrance, California.
point-by-point difference in macular thickness between two scans. Using macular thickness maps, average macular volume (AMV) can be calculated as a quantitative assessment of these volumetric changes (Figure 1).6,7 Herein, we report two cases of GA progression demonstrated with longitudinal imaging studies to highlight the benefits of difference maps and AMV and discuss their potential use in clinical studies.
G
eographic atrophy (GA) is the vision-threatening endpoint of dry age-related macular degeneration. Progression of GA can be assessed two-dimensionally using fundus autofluorescence (FAF),1 fundus photography (FP),2 fluorescein angiography,2 and optical coherence tomography (OCT) fundus images.3 Highresolution optical coherence tomography (HR-OCT) can reveal morphologic changes associated with GA, including temporal decreases in macular thickness.4 In addition, current HR-OCT software (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) offers advanced retinal pigment epithelium (RPE) analysis measuring area based on light reflected beneath the RPE, termed sub-RPE slab.5 Another feature of HR-OCT software is difference maps, which is a topographical map of the
Case Report 1 Seventy-two-year-old Caucasian female with a history of agerelated macular degeneration—wet in the left eye and dry in the right—was noted to have clinical manifestations of GA in the right eye. Her visual acuity corrected to 20/20 in the right eye and 20/200 in the left. She was also noted to have nuclear sclerotic cataracts and primary open-angle glaucoma in both eyes. Color and red-free FP demonstrated extrafoveal areas of partial or complete depigmentation indicative of GA, as confirmed with fluorescein angiography studies (Figure 2, A, C, and E). High-resolution OCT subRPE slab assessment highlighted similar areas of GA and RPE volume measured in the inner 3-mm-diameter circle was 0.11 mm3 while AMV was 2.07 mm3 (Figure 2G). The patient began a vitamin
None of the authors have any financial/conflicting interests to disclose. Reprint requests: Ron Gallemore, MD, PhD, Retina Macula Institute, 4201 Torrance Boulevard Suite 220, Torrance, CA 90503; e-mail: [email protected]
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Fig. 1. Macular thickness map with Early Treatment Diabetic Retinopathy Study subfields of interest highlighted for AMV measurement. The macular thickness values seen in the highlighted segments are averaged then multiplied by the area of this 3-mm-diameter circle to calculate AMV.
regimen, following the Age-Related Eye Disease Study 2 guidelines. The patient was seen 3.5 years later for routine intravitreal anti– vascular endothelial growth factor injection in the left eye. At this time, there was a mild progression of cataracts with stable medical management of her glaucoma and her age-related macular degeneration remained dry in the right eye. Visual acuity was now 20/60−1 in the right eye and 20/80 in the left eye. Color and red-free FP, fluorescein angiography studies, and HR-OCT sub-RPE slab assessment showed GA expansion with foveal involvement (Figure 2, B, D, F, and H). Retinal pigment epithelium volume decreased to 0.02 mm3 and AMV similarly decreased to 1.97 mm3, a 4.8% decrease in macular volume. Difference maps were created and demonstrated macular thinning signified by large green and blue areas (Figure 2M). Comparison of these areas of thinning with other techniques showed these changes to be appreciable both in new and previously visible areas of GA. Some artifactual increases in macular thickness (represented in orange) were also noted.
Case Report 2 Eighty-four-year-old Caucasian female presented for routine examination. She had a history of dry age-related macular degeneration in the left eye and wet in the right eye along with nuclear sclerotic cataracts in both. Visual acuity was counting fingers at 5 feet in the right eye and 20/100−1 in the left eye. Color FP revealed multiple well-demarcated areas of depigmentation (Figure 3A). Fundus autofluorescence documented numerous areas of devitalized or absent pigment epithelium, shown in black, associated with GA, many not documented on color fundus photograph (Figure 3C). High-resolution OCT sub-RPE slab assessment demonstrated similar areas of GA as seen on FAF studies and RPE volume was shown to be 0.00 mm3 while AMV was 1.98 mm3 (Figure 3E). Subsequently, she was enrolled in the
Fig. 2. Case 1: (A and B) color FPs, (C and D) red-free FPs, (E and F) fluorescein angiography, (G and H) HR-OCT sub-RPE slab, (I and J) HR-OCT foveal cross-section, and (K and L) HR-OCT macular thickness maps from baseline (left) and 3.5 years later (right) show GA progression. M. High-resolution OCT difference map demonstrates point-to-point difference in macular thickness topographically with areas of thinning (in green) throughout. Areas of thickening (in orange) are due, in part, to HR-OCT artifacts.
90
RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 1 Geographic Atrophy Treatment Evaluation study to test the efficacy of a topical treatment for GA. Following 2 years of enrollment in the study, cataract surgery in the left eye, and numerous intravitreal anti–vascular endothelial growth factor injections in the right eye, the patient returned for follow-up with a visual acuity of counting fingers at 4 feet in the right eye and 20/60 in the left eye. At this time, color FP, FAF, and HR-OCT sub-RPE slab assessment demonstrated expansion of GA lesions (Figure 3, B, D, and F). Retinal pigment epithelium volume was measured at 0.00 mm3 and AMV was 1.76 mm3, an 11.1% decrease. Difference maps on HR-OCT demonstrated vast areas of green with negative macular thickness changes in all Early Treatment Diabetic Retinopathy Study subfields (Figure 3K). Once again, the areas of thinning were both within areas of expanded GA and areas of previously visible GA on both color FP and FAF.
Discussion
Fig. 3. Case 2: (A and B) color FP, (C and D) FAF, (E and F) HROCT sub-RPE slab, (G and H) HR-OCT foveal cross-section, and (I and J) HR-OCT macular thickness maps from baseline (left) and 2 years later (right) show GA progression. K. High-resolution OCT difference map demonstrates areas of macular thinning (in green) throughout the entire topographical map.
Difference maps and AMV measurements are effective ways to quantify progression of GA. Fundus photography, FAF, and fluorescein angiography also demonstrate GA, but these two-dimensional studies miss the volume effects of GA. Current imaging modalities demonstrate atrophy in the RPE and choriocapillaris but fail to evaluate other retinal layers that may represent a better assessment of GA.1–5 It is well established that photoreceptor atrophy is characteristic of GA, but this feature is not assessed with any other technique.8 Using difference maps allows for the three-dimensional assessment of thinning in all retinal layers from the internal limiting membrane to the RPE. In both of the presented cases, the changes in GA seen by traditional imaging modalities were comparable with areas of retinal thinning on difference maps. In addition, there was progressive thinning on these difference maps within previously well-demarcated areas of GA, possibly relating to further RPE atrophy and otherwise unappreciable photoreceptor loss. Similar to difference maps, AMV calculates the volume of all retinal layers confined to a 3-mm-diameter circle. The decrease in RPE volume as measured on HR-OCT fails to completely explain the AMV change, supporting the need to monitor additional retinal layers. Moreover, in the second case presented, RPE volume failed to provide any information because it was measured at 0.00 mm3 at baseline and follow-up. Limitations still exist with current HR-OCT technology and the accuracy of macular thickness measurements. Outer and inner retinal layer misidentification is a fairly common occurrence with current HR-OCT software,9 which can result in erroneous measurements within portions of difference maps (Figure 2M). In addition, HR-OCT images routinely fail to be appropriately centered over the fovea, limiting AMV and
91
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difference map comparisons to only the inner 3-mm circle. Other limitations confounding these techniques include thinning of inner retinal layers secondary to atherosclerosis, vascular disease, and glaucoma. One patient in our study had controlled glaucoma while the other did not have glaucoma, but both were otherwise healthy. The areas of atrophy witnessed are consistent with loss from GA, but uncontrolled glaucoma can also cause nerve fiber layer loss. Therefore, a randomized controlled study might be required to elucidate the potential contributions of other causes of volume loss. Such factors should be considered when analyzing these data and when using this technique in clinical trials. With more advanced GA, loss of inner retinal layer structures can also occur,4 so in some ways AMV analysis may provide a better picture of overall retinal health rather than assessing outer retinal layer structures alone.3,5 In practical terms, the difference map may prove to be a more sensitive and simple way of measuring loss of retinal structure, but eventually combining these techniques with the assessment of specific layers would be ideal. Difference maps and AMV are novel endpoints for current GA research, adding to the information provided by two-dimensional studies. Key words: age-related macular degeneration, geographic atrophy, optical coherence tomography.
References 1. Bearelly S, Khanifar AA, Lederer DE, et al. Use of fundus autofluorescence images to predict geographic atrophy progression. Retina 31:81–86. 2. Brader HS, Ying G, Martin ER, et al. New grading criteria allow for earlier detection of geographic atrophy in clinical trials. Invest Ophthalmol Vis Sci 2011;52:9218–9225. 3. Yehoshua Z, Rosenfeld PJ, Gregori G, et al. Progression of geographic atrophy in age-related macular degeneration imaged with spectral domain optical coherence tomography. Ophthalmology 2011;118:679–686. 4. Wolf-Schnurrbusch UEK, Enzmann V, Brinkmann CK, Wolf S. Morphologic changes in patients with geographic atrophy assessed with a novel spectral OCT-SLO combination. Invest Ophthalmol Vis Sci 2008;49:3095–3099. 5. Yehoshua Z, Garcia Filho CAA, Penha F, et al. Comparison of geographic atrophy measurements from the OCT fundus image and the sub-RPE slab image. Ophthalmic Surg Lasers Imaging Retina 2013;44:127–132. 6. Gallemore RP, Wallsh JO, Eells M. A new endpoint for longitudinal measurements of geographic atrophy. Poster session presented at: 29th Annual Meeting of the American Society of Retina Specialists; August 20–24, 2011; Boston, MA. 7. Wallsh JO, Gallemore RP. Average macular volume over time in patients with geographic atrophy measured with high-resolution OCT: a new End Point for clinical trials. Poster session presented at: 115th Annual Meeting of the American Academy of Ophthalmologists; October 22–25, 2011; Orlando, FL. 8. Sarks SH. Ageing and degeneration in the macular region: a clinico-pathological study. Br J Ophthalmol 1976;60:324–341. 9. Ho J, Sull AC, Vuong LN, et al. Assessment of artifacts and reproducibility across spectral- and time-domain optical coherence tomography devices. Ophthalmology 2009;116:1960–1970.
Purpose: To demonstrate the ability to monitor geographic atrophy (GA) volumetrically through all retinal layers with high-resolution optical coherence tomography difference maps and average macular volume. Methods: Observational case report. Results: Two patients diagnosed with GA were followed up for multiple years with consecutive high-resolution optical coherence tomography studies along with fundus photography and fluorescein angiography or fundus autofluorescence. Difference maps visually reflect macular thinning associated with expansion of GA witnessed on alternative studies. In addition, these maps show progressive macular thinning within previously delineated areas of GA. Average macular volume quantitatively demonstrates the decreasing volume associated with the expanding atrophy. Conclusion: Difference maps and average macular volume allow quantitative analysis of GA and may be a useful tool for patient care and clinical trials. RETINAL CASES & BRIEF REPORTS 9:88–91, 2015
From the Retina Macula Institute, Torrance, California.
point-by-point difference in macular thickness between two scans. Using macular thickness maps, average macular volume (AMV) can be calculated as a quantitative assessment of these volumetric changes (Figure 1).6,7 Herein, we report two cases of GA progression demonstrated with longitudinal imaging studies to highlight the benefits of difference maps and AMV and discuss their potential use in clinical studies.
G
eographic atrophy (GA) is the vision-threatening endpoint of dry age-related macular degeneration. Progression of GA can be assessed two-dimensionally using fundus autofluorescence (FAF),1 fundus photography (FP),2 fluorescein angiography,2 and optical coherence tomography (OCT) fundus images.3 Highresolution optical coherence tomography (HR-OCT) can reveal morphologic changes associated with GA, including temporal decreases in macular thickness.4 In addition, current HR-OCT software (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) offers advanced retinal pigment epithelium (RPE) analysis measuring area based on light reflected beneath the RPE, termed sub-RPE slab.5 Another feature of HR-OCT software is difference maps, which is a topographical map of the
Case Report 1 Seventy-two-year-old Caucasian female with a history of agerelated macular degeneration—wet in the left eye and dry in the right—was noted to have clinical manifestations of GA in the right eye. Her visual acuity corrected to 20/20 in the right eye and 20/200 in the left. She was also noted to have nuclear sclerotic cataracts and primary open-angle glaucoma in both eyes. Color and red-free FP demonstrated extrafoveal areas of partial or complete depigmentation indicative of GA, as confirmed with fluorescein angiography studies (Figure 2, A, C, and E). High-resolution OCT subRPE slab assessment highlighted similar areas of GA and RPE volume measured in the inner 3-mm-diameter circle was 0.11 mm3 while AMV was 2.07 mm3 (Figure 2G). The patient began a vitamin
None of the authors have any financial/conflicting interests to disclose. Reprint requests: Ron Gallemore, MD, PhD, Retina Macula Institute, 4201 Torrance Boulevard Suite 220, Torrance, CA 90503; e-mail: [email protected]
88
OCT FOR GEOGRAPHIC ATROPHY
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Fig. 1. Macular thickness map with Early Treatment Diabetic Retinopathy Study subfields of interest highlighted for AMV measurement. The macular thickness values seen in the highlighted segments are averaged then multiplied by the area of this 3-mm-diameter circle to calculate AMV.
regimen, following the Age-Related Eye Disease Study 2 guidelines. The patient was seen 3.5 years later for routine intravitreal anti– vascular endothelial growth factor injection in the left eye. At this time, there was a mild progression of cataracts with stable medical management of her glaucoma and her age-related macular degeneration remained dry in the right eye. Visual acuity was now 20/60−1 in the right eye and 20/80 in the left eye. Color and red-free FP, fluorescein angiography studies, and HR-OCT sub-RPE slab assessment showed GA expansion with foveal involvement (Figure 2, B, D, F, and H). Retinal pigment epithelium volume decreased to 0.02 mm3 and AMV similarly decreased to 1.97 mm3, a 4.8% decrease in macular volume. Difference maps were created and demonstrated macular thinning signified by large green and blue areas (Figure 2M). Comparison of these areas of thinning with other techniques showed these changes to be appreciable both in new and previously visible areas of GA. Some artifactual increases in macular thickness (represented in orange) were also noted.
Case Report 2 Eighty-four-year-old Caucasian female presented for routine examination. She had a history of dry age-related macular degeneration in the left eye and wet in the right eye along with nuclear sclerotic cataracts in both. Visual acuity was counting fingers at 5 feet in the right eye and 20/100−1 in the left eye. Color FP revealed multiple well-demarcated areas of depigmentation (Figure 3A). Fundus autofluorescence documented numerous areas of devitalized or absent pigment epithelium, shown in black, associated with GA, many not documented on color fundus photograph (Figure 3C). High-resolution OCT sub-RPE slab assessment demonstrated similar areas of GA as seen on FAF studies and RPE volume was shown to be 0.00 mm3 while AMV was 1.98 mm3 (Figure 3E). Subsequently, she was enrolled in the
Fig. 2. Case 1: (A and B) color FPs, (C and D) red-free FPs, (E and F) fluorescein angiography, (G and H) HR-OCT sub-RPE slab, (I and J) HR-OCT foveal cross-section, and (K and L) HR-OCT macular thickness maps from baseline (left) and 3.5 years later (right) show GA progression. M. High-resolution OCT difference map demonstrates point-to-point difference in macular thickness topographically with areas of thinning (in green) throughout. Areas of thickening (in orange) are due, in part, to HR-OCT artifacts.
90
RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 1 Geographic Atrophy Treatment Evaluation study to test the efficacy of a topical treatment for GA. Following 2 years of enrollment in the study, cataract surgery in the left eye, and numerous intravitreal anti–vascular endothelial growth factor injections in the right eye, the patient returned for follow-up with a visual acuity of counting fingers at 4 feet in the right eye and 20/60 in the left eye. At this time, color FP, FAF, and HR-OCT sub-RPE slab assessment demonstrated expansion of GA lesions (Figure 3, B, D, and F). Retinal pigment epithelium volume was measured at 0.00 mm3 and AMV was 1.76 mm3, an 11.1% decrease. Difference maps on HR-OCT demonstrated vast areas of green with negative macular thickness changes in all Early Treatment Diabetic Retinopathy Study subfields (Figure 3K). Once again, the areas of thinning were both within areas of expanded GA and areas of previously visible GA on both color FP and FAF.
Discussion
Fig. 3. Case 2: (A and B) color FP, (C and D) FAF, (E and F) HROCT sub-RPE slab, (G and H) HR-OCT foveal cross-section, and (I and J) HR-OCT macular thickness maps from baseline (left) and 2 years later (right) show GA progression. K. High-resolution OCT difference map demonstrates areas of macular thinning (in green) throughout the entire topographical map.
Difference maps and AMV measurements are effective ways to quantify progression of GA. Fundus photography, FAF, and fluorescein angiography also demonstrate GA, but these two-dimensional studies miss the volume effects of GA. Current imaging modalities demonstrate atrophy in the RPE and choriocapillaris but fail to evaluate other retinal layers that may represent a better assessment of GA.1–5 It is well established that photoreceptor atrophy is characteristic of GA, but this feature is not assessed with any other technique.8 Using difference maps allows for the three-dimensional assessment of thinning in all retinal layers from the internal limiting membrane to the RPE. In both of the presented cases, the changes in GA seen by traditional imaging modalities were comparable with areas of retinal thinning on difference maps. In addition, there was progressive thinning on these difference maps within previously well-demarcated areas of GA, possibly relating to further RPE atrophy and otherwise unappreciable photoreceptor loss. Similar to difference maps, AMV calculates the volume of all retinal layers confined to a 3-mm-diameter circle. The decrease in RPE volume as measured on HR-OCT fails to completely explain the AMV change, supporting the need to monitor additional retinal layers. Moreover, in the second case presented, RPE volume failed to provide any information because it was measured at 0.00 mm3 at baseline and follow-up. Limitations still exist with current HR-OCT technology and the accuracy of macular thickness measurements. Outer and inner retinal layer misidentification is a fairly common occurrence with current HR-OCT software,9 which can result in erroneous measurements within portions of difference maps (Figure 2M). In addition, HR-OCT images routinely fail to be appropriately centered over the fovea, limiting AMV and
91
OCT FOR GEOGRAPHIC ATROPHY
difference map comparisons to only the inner 3-mm circle. Other limitations confounding these techniques include thinning of inner retinal layers secondary to atherosclerosis, vascular disease, and glaucoma. One patient in our study had controlled glaucoma while the other did not have glaucoma, but both were otherwise healthy. The areas of atrophy witnessed are consistent with loss from GA, but uncontrolled glaucoma can also cause nerve fiber layer loss. Therefore, a randomized controlled study might be required to elucidate the potential contributions of other causes of volume loss. Such factors should be considered when analyzing these data and when using this technique in clinical trials. With more advanced GA, loss of inner retinal layer structures can also occur,4 so in some ways AMV analysis may provide a better picture of overall retinal health rather than assessing outer retinal layer structures alone.3,5 In practical terms, the difference map may prove to be a more sensitive and simple way of measuring loss of retinal structure, but eventually combining these techniques with the assessment of specific layers would be ideal. Difference maps and AMV are novel endpoints for current GA research, adding to the information provided by two-dimensional studies. Key words: age-related macular degeneration, geographic atrophy, optical coherence tomography.
References 1. Bearelly S, Khanifar AA, Lederer DE, et al. Use of fundus autofluorescence images to predict geographic atrophy progression. Retina 31:81–86. 2. Brader HS, Ying G, Martin ER, et al. New grading criteria allow for earlier detection of geographic atrophy in clinical trials. Invest Ophthalmol Vis Sci 2011;52:9218–9225. 3. Yehoshua Z, Rosenfeld PJ, Gregori G, et al. Progression of geographic atrophy in age-related macular degeneration imaged with spectral domain optical coherence tomography. Ophthalmology 2011;118:679–686. 4. Wolf-Schnurrbusch UEK, Enzmann V, Brinkmann CK, Wolf S. Morphologic changes in patients with geographic atrophy assessed with a novel spectral OCT-SLO combination. Invest Ophthalmol Vis Sci 2008;49:3095–3099. 5. Yehoshua Z, Garcia Filho CAA, Penha F, et al. Comparison of geographic atrophy measurements from the OCT fundus image and the sub-RPE slab image. Ophthalmic Surg Lasers Imaging Retina 2013;44:127–132. 6. Gallemore RP, Wallsh JO, Eells M. A new endpoint for longitudinal measurements of geographic atrophy. Poster session presented at: 29th Annual Meeting of the American Society of Retina Specialists; August 20–24, 2011; Boston, MA. 7. Wallsh JO, Gallemore RP. Average macular volume over time in patients with geographic atrophy measured with high-resolution OCT: a new End Point for clinical trials. Poster session presented at: 115th Annual Meeting of the American Academy of Ophthalmologists; October 22–25, 2011; Orlando, FL. 8. Sarks SH. Ageing and degeneration in the macular region: a clinico-pathological study. Br J Ophthalmol 1976;60:324–341. 9. Ho J, Sull AC, Vuong LN, et al. Assessment of artifacts and reproducibility across spectral- and time-domain optical coherence tomography devices. Ophthalmology 2009;116:1960–1970.
