■
C A S E
Imaging Areas of Retinal Nonperfusion in Ischemic Branch Retinal Vein Occlusion With Swept-Source OCT Microangiography Laura Kuehlewein, MD; Lin An, PhD; Mary K. Durbin, PhD; SriniVas R. Sadda MD
ABSTRACT: The authors present the case of a patient with a history of ischemic branch vein occlusion and multimodal imaging of the retinal vasculature by fluorescein angiography (FA) and ultrahigh-speed sweptsource optical coherence tomography (SS-OCT) microangiography (SS-OCT laser prototype; 1,050 nm, 100,000 A-scans/second). Multiple images across the macula were acquired (3 × 3 mm cubes in clusters of four repeated B-scans). En face images of the vasculature were generated by implementing an intensity differentiation algorithm. The retinal vasculature as well areas of nonperfusion could be identified precisely at multiple retinal levels. Ultrahigh-speed SSOCT microangiography provides noninvasive, threedimensional, high-resolution images of the retinal vasculature including the capillaries. [Ophthalmic Surg Lasers Imaging Retina. 2015;46:249-252.]
From the Doheny Eye Institute, Los Angeles, California (LK, SRS); the Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California (LK, SRS); and Carl Zeiss Meditec, Dublin, California (LA, MKD). Originally submitted October 7, 2014. Accepted for publication November 21, 2014. Dr. Sadda is a consultant for Allergan, Carl Zeiss Meditec, Genentech, Optos, and Optovue. The remaining authors have no financial or propriety interest in the materials presented herein. Address correspondence to SriniVas R. Sadda, MD, Doheny Eye Institute, 1450 San Pablo Street, Los Angeles, CA 90033; 323-442-6393; email: [email protected]. doi: 10.3928/23258160-20150213-19
February 2015 · Vol. 46, No. 2
R E P O R T
■
INTRODUCTION
Optical coherence tomography (OCT) has revolutionized imaging of the retina since its introduction in the early 1990s.1,2 More recently, there has been an increased interest in generating detailed images of the retinal vasculature using OCT. OCT, aside from being a noninvasive and comfortable imaging method for the patient, can simultaneously provide high-resolution (micron-level) and three-dimensional information on the morphology of the retina and associated tissues. OCT microangiography (OMAG) images visualizing specifically the vasculature including the capillaries can be generated by capturing a series of B-scans in the same location, allowing the isolation of motion (blood flow) signals from static (tissue) signals.3 Microcirculation imaging has profited from recent technological developments in OCT technology, namely the implementation of swept-source (SS) laser and ultrahigh-speed frequency-domain OCT.4-6 CASE REPORT
We present the case of a 67-year-old woman with a history of ischemic superotemporal branch vein occlusion in the left eye occurring in late 2009. Informed consent was obtained from the patient, and the case report complies with institutional review board regulations and the requirements of the Declaration of Helsinki. Fluorescein angiography at presentation revealed extensive areas of peripheral retinal nonperfusion. The patient’s medical history was notable only for hypertension treated orally with atenolol. In 2010, she developed an area of retinal neovascularization, which prompted scatter panretinal photocoagulation (PRP). Treatment of the associated macular edema included macular grid laser as well as multiple (every 4 to 6 weeks) intravitreal injections of bevacizumab, ranibizumab, and aflibercept. An epiretinal membrane (ERM) was also thought to be contributing to her persistent edema, and pars plana vitrectomy with peeling of ERM and internal limiting membrane (ILM) was also performed, followed by cataract surgery. Although the macular edema has improved compared to initial presentation, the patient has followed a chronic course with recurrent edema requiring therapy. At the most recent examination, the patient’s best corrected visual acuity (BCVA) was 20/40 in the affected left eye, with no improvement on pinhole; the intraocular pressure was 13 mm Hg. Anterior segment
249
A
B
C
D
Figure 1. (A) Color fundus photography. (B) Early and (C) late fluorescein angiography (FA) frames (Topcon Retinal Camera; Topcon Medical Systems, Oakland, NJ). (D) Optical coherence tomography, horizontal and vertical central B-scans (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA).
A
B
Figure 2. (A) Fluorescein angiography (FA) of the left eye at 0:54 min. Status post ischemic branch vein occlusion with areas of retinal non-perfusion superotemporal and temporal of the macula (arrows), collaterals, microaneurysms, and leakage (Topcon Retinal Camera; Topcon Medical Systems, Oakland, NJ). (B) OCT microangiography montage showing the foveal avascular zone, larger and smaller blood vessels including the capillary network, and absence of blood flow superotemporally consistent with areas of nonperfusion in FA (swept-source OCT prototype; Carl Zeiss Meditec, Dublin, CA).
evaluation was notable only for a well-centered posterior chamber intraocular lens in the capsular bag. No neovascularization of the iris was observed. Dilated fundus examination of the left eye revealed peripheral PRP laser scars, sclerotic peripheral vessels, macular microaneurysms and telangiectatic vessels, and cystoid macular edema (Figure 1).
SS-OCT images were acquired using a prototype swept-source laser OCT (510K clearance pending) from Carl Zeiss Meditec (Dublin, CA), with a central wavelength of 1,050 nm (1,000 to 1,100 nm full width) and a speed of 100,000 A-scans per second. For SSOCT microangiography imaging, 3 × 3 × 3 mm cubes were acquired, each cube consisting of 300 clusters of four repeated B-scans containing 300 A-scans each. Multiple cubes were obtained in the posterior pole, including centered on the fovea as well in additional regions temporally and superotemporally. Each recording took 4.5 seconds. A proprietary intensity dif-
ferentiation algorithm was applied to extract in vivo blood flow information.7,8 Details of this algorithm are not publicly available. Automated algorithms based on existing segmentation techniques used in the Cirrus OCT (Carl Zeiss Meditec) were used to identify the retinal pigment epithelium (RPE) and inner limiting membrane (ILM) in the OCT intensity image. To delineate the best plane to separate the superficial and deeper retinal capillaries, we first generated a rough estimate of the position of the outer border of the plexiform layer as approximately 55 pixels internal to the RPE.9 Although photoreceptor and outer nuclear layer edema or thinning could confound this threshold, this approximation seemed to be acceptable for this case. The neurosensory retina internal to this boundary was designated to be the “inner retina” and was further divided empirically into “superficial” (inner 60%) and “deeper” (outer 40%) retinal capillary layers. En face images of the vasculature were generated by a maximum intensity projection for the identified layers.
250
Ophthalmic Surgery, Lasers & Imaging Retina | Healio.com/OSLIRetina
Imaging
A
D
G
B
E
H
C
F
I
Figure 3. Side-by-side inspection of fluorescein angiography (FA) and OCT microangiography (OMAG). Detail of FA imaging of the left eye at 00:54 min showing the (A) region superior of the macula, (B) macular region, and (C) region temporal of the macula. (D-I) OMAG showing en face summation images of the retinal blood vessels and microvascular network in the regions corresponding to the regions in A-C in selected retinal layers. D-F represent the blood vessels located in the superficial retinal capillary layer, and G-I represent the blood vessels located in the deeper retinal capillary layer, respectively. (E,H) Foveal avascular zone in OMAG imaging. (D-I) Absence of blood flow in areas consistent with areas of non-perfusion in FA. The borders of nonperfusion differ slightly at the two levels.
Using this approach, we obtained detailed, depthresolved images of the retinal vasculature in the posterior pole. The correspondence between the microcirculation by FA and OMAG was assessed using side-by-side inspection as well as overlay of the images (Figures 2 and 3). DISCUSSION
In this report, we present the case of a patient with history of ischemic branch vein occlusion in whom multimodal imaging of the retinal vasculature was performed by FA and SS-OCT microangiography. Overall greater detail in the capillary circulation was observed in the OMAG images. The borders of areas of perfusion and nonperfusion were also sharply demarcated on the OMAG images. They seemed to correspond precisely with the FA, suggesting that the approach may be useful for evaluating perfusion defects in eyes with retinal vascular disease.
February 2015 · Vol. 46, No. 2
Even in the absence of tracking, the rapid acquisition speed of the SS-OCT device allowed the OMAG images to be acquired at high scan density without significant motion artifact or banding often seen with SD-OCT–based OCT angiography acquisitions. This patient, however, had good central fixation and a visual acuity of 20/40. For patients with poorer levels of vision and fixation, tracking will likely be required in order to obtain high-quality OMAG images. OMAG images, however, failed to demonstrate evidence of leakage that was evident on FA. On the other hand, en-face OMAG images allowed the retinal microcirculation to be imaged at separate planes, with the superficial and deeper portions of the inner retina revealing that the nonperfusion extended through the entire inner retina although the borders between perfused and nonperfused retina at the two levels differed slightly. The separation between “superficial” and “deep” portions of the circulation was somewhat arbitrarily selected but is similar to what has been
251
described in previous histology studies.10 Selective visualization of the deep retinal capillary plexus is of interest, because recent reports have identified diseases featuring isolated deep capillary ischemia.11 Although there would appear to be many advantages of OMAG including its rapid and comfortable acquisition, depth resolution, lack of invasive dye injection, and excellent microvascular resolution, the technique is not without significant limitations. These drawbacks include a small field of view (3 × 3 mm in this case), motion artifact in poorly fixating patients, and the absence of dynamic (transit time, speed of flow) and vascular leakage information. The field of view limitation could be overcome by obtaining multiple scans followed by montage, and inclusion of eye tracking could address motion artifact (though higher-speed tracking techniques may be required). Flow velocity information could potentially be extracted using complementary Doppler OCT techniques, but these quantitative assessments may be limited to the larger retinal vessels. Leakage, however, is perhaps the most critically important of these and is relevant to a wide variety of retinal and choroidal vascular diseases. It may eventually be possible to identify leakage on OMAG images by isolating very slow “flow,” but this has yet to be demonstrated. Until these limitations can be addressed, FA will likely continue to have an important role in the diagnosis and management of patients with retinal and choroidal vascular diseases. In summary, ultrahigh-speed swept-source OCT microangiography provides noninvasive, three-dimensional high-resolution images of the retinal vasculature including the capillary circulation. Areas of retinal nonperfusion can be delineated with precision
and at multiple retinal levels. With further improvements, OCT microangiography may eventually reduce the need for conventional fluorescein angiography.
252
Ophthalmic Surgery, Lasers & Imaging Retina | Healio.com/OSLIRetina
REFERENCES 1. van Velthoven ME, Faber DJ, Verbraak FD, van Leeuwen TG, de Smet MD. Recent developments in optical coherence tomography for imaging the retina. Prog Retin Eye Res. 2007;26(1):57-77. 2. Gabriele ML, Wollstein G, Ishikawa H, et al. Optical Coherence Tomography: History, Current Status, and Laboratory Work. Invest Ophthalmol Vis Sci. 2011;52(5):2425–2436. 3. Fingler J, Zawadzki RJ, Werner JS, Schwartz D, Fraser SE. Volumetric microvascular imaging of human retina using optical coherence tomography with a novel motion contrast technique. Opt Express. 2009;17(24):22190-22200. 4. Huber R, Adler DC, Srinivasan VJ, Fujimoto JG. Fourier domain mode locking at 1050 nm for ultra-high-speed optical coherence tomography of the human retina at 236,000 axial scans per second. Opt Lett. 2007;32(14):2049-2051. 5. Schmoll T, Kolbitsch C, Leitgeb RA. Ultra-high-speed volumetric tomography of human retinal blood flow. Opt Express. 2009;17(5):41664176. 6. An L, Shen TT, Wang RK. Using ultrahigh sensitive optical microangiography to achieve comprehensive depth resolved microvasculature mapping for human retina. J Biomed Opt. 2011;16(10):106013. 7. Wang RK, Jacques SL, Ma Z, Hurst S, Hanson SR, Gruber A. Three dimensional optical angiography. Opt Express. 2007;15(7):40834097. 8. Huang Y, Zhang Q, Thorell MR, et al. Swept-Source OCT Angiography of the Retinal Vasculature Using Intensity Differentiation-based Optical Microangiography Algorithms. Ophthalmic Surg Lasers Imaging Retina. 2014;1-8. 9. Bagci AM, Shahidi M, Ansari R, Blair M, Blair NP, Zelkha R. Thickness profiles of retinal layers by optical coherence tomography image segmentation. Am J Ophthalmol. 2008;146(5):679-687. 10. Tan PE, Yu PK, Balaratnasingam C, et al. Quantitative confocal imaging of the retinal microvasculature in the human retina. Invest Ophthalmol Vis Sci. 2012;53(9):5728-5736. 11. Sarraf D, Rahimy E, Fawzi AA, et al. Paracentral acute middle maculopathy: a new variant of acute macular neuroretinopathy associated with retinal capillary ischemia. JAMA Ophthalmol. 2013;131(10):1275-1287.
C A S E
Imaging Areas of Retinal Nonperfusion in Ischemic Branch Retinal Vein Occlusion With Swept-Source OCT Microangiography Laura Kuehlewein, MD; Lin An, PhD; Mary K. Durbin, PhD; SriniVas R. Sadda MD
ABSTRACT: The authors present the case of a patient with a history of ischemic branch vein occlusion and multimodal imaging of the retinal vasculature by fluorescein angiography (FA) and ultrahigh-speed sweptsource optical coherence tomography (SS-OCT) microangiography (SS-OCT laser prototype; 1,050 nm, 100,000 A-scans/second). Multiple images across the macula were acquired (3 × 3 mm cubes in clusters of four repeated B-scans). En face images of the vasculature were generated by implementing an intensity differentiation algorithm. The retinal vasculature as well areas of nonperfusion could be identified precisely at multiple retinal levels. Ultrahigh-speed SSOCT microangiography provides noninvasive, threedimensional, high-resolution images of the retinal vasculature including the capillaries. [Ophthalmic Surg Lasers Imaging Retina. 2015;46:249-252.]
From the Doheny Eye Institute, Los Angeles, California (LK, SRS); the Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California (LK, SRS); and Carl Zeiss Meditec, Dublin, California (LA, MKD). Originally submitted October 7, 2014. Accepted for publication November 21, 2014. Dr. Sadda is a consultant for Allergan, Carl Zeiss Meditec, Genentech, Optos, and Optovue. The remaining authors have no financial or propriety interest in the materials presented herein. Address correspondence to SriniVas R. Sadda, MD, Doheny Eye Institute, 1450 San Pablo Street, Los Angeles, CA 90033; 323-442-6393; email: [email protected]. doi: 10.3928/23258160-20150213-19
February 2015 · Vol. 46, No. 2
R E P O R T
■
INTRODUCTION
Optical coherence tomography (OCT) has revolutionized imaging of the retina since its introduction in the early 1990s.1,2 More recently, there has been an increased interest in generating detailed images of the retinal vasculature using OCT. OCT, aside from being a noninvasive and comfortable imaging method for the patient, can simultaneously provide high-resolution (micron-level) and three-dimensional information on the morphology of the retina and associated tissues. OCT microangiography (OMAG) images visualizing specifically the vasculature including the capillaries can be generated by capturing a series of B-scans in the same location, allowing the isolation of motion (blood flow) signals from static (tissue) signals.3 Microcirculation imaging has profited from recent technological developments in OCT technology, namely the implementation of swept-source (SS) laser and ultrahigh-speed frequency-domain OCT.4-6 CASE REPORT
We present the case of a 67-year-old woman with a history of ischemic superotemporal branch vein occlusion in the left eye occurring in late 2009. Informed consent was obtained from the patient, and the case report complies with institutional review board regulations and the requirements of the Declaration of Helsinki. Fluorescein angiography at presentation revealed extensive areas of peripheral retinal nonperfusion. The patient’s medical history was notable only for hypertension treated orally with atenolol. In 2010, she developed an area of retinal neovascularization, which prompted scatter panretinal photocoagulation (PRP). Treatment of the associated macular edema included macular grid laser as well as multiple (every 4 to 6 weeks) intravitreal injections of bevacizumab, ranibizumab, and aflibercept. An epiretinal membrane (ERM) was also thought to be contributing to her persistent edema, and pars plana vitrectomy with peeling of ERM and internal limiting membrane (ILM) was also performed, followed by cataract surgery. Although the macular edema has improved compared to initial presentation, the patient has followed a chronic course with recurrent edema requiring therapy. At the most recent examination, the patient’s best corrected visual acuity (BCVA) was 20/40 in the affected left eye, with no improvement on pinhole; the intraocular pressure was 13 mm Hg. Anterior segment
249
A
B
C
D
Figure 1. (A) Color fundus photography. (B) Early and (C) late fluorescein angiography (FA) frames (Topcon Retinal Camera; Topcon Medical Systems, Oakland, NJ). (D) Optical coherence tomography, horizontal and vertical central B-scans (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA).
A
B
Figure 2. (A) Fluorescein angiography (FA) of the left eye at 0:54 min. Status post ischemic branch vein occlusion with areas of retinal non-perfusion superotemporal and temporal of the macula (arrows), collaterals, microaneurysms, and leakage (Topcon Retinal Camera; Topcon Medical Systems, Oakland, NJ). (B) OCT microangiography montage showing the foveal avascular zone, larger and smaller blood vessels including the capillary network, and absence of blood flow superotemporally consistent with areas of nonperfusion in FA (swept-source OCT prototype; Carl Zeiss Meditec, Dublin, CA).
evaluation was notable only for a well-centered posterior chamber intraocular lens in the capsular bag. No neovascularization of the iris was observed. Dilated fundus examination of the left eye revealed peripheral PRP laser scars, sclerotic peripheral vessels, macular microaneurysms and telangiectatic vessels, and cystoid macular edema (Figure 1).
SS-OCT images were acquired using a prototype swept-source laser OCT (510K clearance pending) from Carl Zeiss Meditec (Dublin, CA), with a central wavelength of 1,050 nm (1,000 to 1,100 nm full width) and a speed of 100,000 A-scans per second. For SSOCT microangiography imaging, 3 × 3 × 3 mm cubes were acquired, each cube consisting of 300 clusters of four repeated B-scans containing 300 A-scans each. Multiple cubes were obtained in the posterior pole, including centered on the fovea as well in additional regions temporally and superotemporally. Each recording took 4.5 seconds. A proprietary intensity dif-
ferentiation algorithm was applied to extract in vivo blood flow information.7,8 Details of this algorithm are not publicly available. Automated algorithms based on existing segmentation techniques used in the Cirrus OCT (Carl Zeiss Meditec) were used to identify the retinal pigment epithelium (RPE) and inner limiting membrane (ILM) in the OCT intensity image. To delineate the best plane to separate the superficial and deeper retinal capillaries, we first generated a rough estimate of the position of the outer border of the plexiform layer as approximately 55 pixels internal to the RPE.9 Although photoreceptor and outer nuclear layer edema or thinning could confound this threshold, this approximation seemed to be acceptable for this case. The neurosensory retina internal to this boundary was designated to be the “inner retina” and was further divided empirically into “superficial” (inner 60%) and “deeper” (outer 40%) retinal capillary layers. En face images of the vasculature were generated by a maximum intensity projection for the identified layers.
250
Ophthalmic Surgery, Lasers & Imaging Retina | Healio.com/OSLIRetina
Imaging
A
D
G
B
E
H
C
F
I
Figure 3. Side-by-side inspection of fluorescein angiography (FA) and OCT microangiography (OMAG). Detail of FA imaging of the left eye at 00:54 min showing the (A) region superior of the macula, (B) macular region, and (C) region temporal of the macula. (D-I) OMAG showing en face summation images of the retinal blood vessels and microvascular network in the regions corresponding to the regions in A-C in selected retinal layers. D-F represent the blood vessels located in the superficial retinal capillary layer, and G-I represent the blood vessels located in the deeper retinal capillary layer, respectively. (E,H) Foveal avascular zone in OMAG imaging. (D-I) Absence of blood flow in areas consistent with areas of non-perfusion in FA. The borders of nonperfusion differ slightly at the two levels.
Using this approach, we obtained detailed, depthresolved images of the retinal vasculature in the posterior pole. The correspondence between the microcirculation by FA and OMAG was assessed using side-by-side inspection as well as overlay of the images (Figures 2 and 3). DISCUSSION
In this report, we present the case of a patient with history of ischemic branch vein occlusion in whom multimodal imaging of the retinal vasculature was performed by FA and SS-OCT microangiography. Overall greater detail in the capillary circulation was observed in the OMAG images. The borders of areas of perfusion and nonperfusion were also sharply demarcated on the OMAG images. They seemed to correspond precisely with the FA, suggesting that the approach may be useful for evaluating perfusion defects in eyes with retinal vascular disease.
February 2015 · Vol. 46, No. 2
Even in the absence of tracking, the rapid acquisition speed of the SS-OCT device allowed the OMAG images to be acquired at high scan density without significant motion artifact or banding often seen with SD-OCT–based OCT angiography acquisitions. This patient, however, had good central fixation and a visual acuity of 20/40. For patients with poorer levels of vision and fixation, tracking will likely be required in order to obtain high-quality OMAG images. OMAG images, however, failed to demonstrate evidence of leakage that was evident on FA. On the other hand, en-face OMAG images allowed the retinal microcirculation to be imaged at separate planes, with the superficial and deeper portions of the inner retina revealing that the nonperfusion extended through the entire inner retina although the borders between perfused and nonperfused retina at the two levels differed slightly. The separation between “superficial” and “deep” portions of the circulation was somewhat arbitrarily selected but is similar to what has been
251
described in previous histology studies.10 Selective visualization of the deep retinal capillary plexus is of interest, because recent reports have identified diseases featuring isolated deep capillary ischemia.11 Although there would appear to be many advantages of OMAG including its rapid and comfortable acquisition, depth resolution, lack of invasive dye injection, and excellent microvascular resolution, the technique is not without significant limitations. These drawbacks include a small field of view (3 × 3 mm in this case), motion artifact in poorly fixating patients, and the absence of dynamic (transit time, speed of flow) and vascular leakage information. The field of view limitation could be overcome by obtaining multiple scans followed by montage, and inclusion of eye tracking could address motion artifact (though higher-speed tracking techniques may be required). Flow velocity information could potentially be extracted using complementary Doppler OCT techniques, but these quantitative assessments may be limited to the larger retinal vessels. Leakage, however, is perhaps the most critically important of these and is relevant to a wide variety of retinal and choroidal vascular diseases. It may eventually be possible to identify leakage on OMAG images by isolating very slow “flow,” but this has yet to be demonstrated. Until these limitations can be addressed, FA will likely continue to have an important role in the diagnosis and management of patients with retinal and choroidal vascular diseases. In summary, ultrahigh-speed swept-source OCT microangiography provides noninvasive, three-dimensional high-resolution images of the retinal vasculature including the capillary circulation. Areas of retinal nonperfusion can be delineated with precision
and at multiple retinal levels. With further improvements, OCT microangiography may eventually reduce the need for conventional fluorescein angiography.
252
Ophthalmic Surgery, Lasers & Imaging Retina | Healio.com/OSLIRetina
REFERENCES 1. van Velthoven ME, Faber DJ, Verbraak FD, van Leeuwen TG, de Smet MD. Recent developments in optical coherence tomography for imaging the retina. Prog Retin Eye Res. 2007;26(1):57-77. 2. Gabriele ML, Wollstein G, Ishikawa H, et al. Optical Coherence Tomography: History, Current Status, and Laboratory Work. Invest Ophthalmol Vis Sci. 2011;52(5):2425–2436. 3. Fingler J, Zawadzki RJ, Werner JS, Schwartz D, Fraser SE. Volumetric microvascular imaging of human retina using optical coherence tomography with a novel motion contrast technique. Opt Express. 2009;17(24):22190-22200. 4. Huber R, Adler DC, Srinivasan VJ, Fujimoto JG. Fourier domain mode locking at 1050 nm for ultra-high-speed optical coherence tomography of the human retina at 236,000 axial scans per second. Opt Lett. 2007;32(14):2049-2051. 5. Schmoll T, Kolbitsch C, Leitgeb RA. Ultra-high-speed volumetric tomography of human retinal blood flow. Opt Express. 2009;17(5):41664176. 6. An L, Shen TT, Wang RK. Using ultrahigh sensitive optical microangiography to achieve comprehensive depth resolved microvasculature mapping for human retina. J Biomed Opt. 2011;16(10):106013. 7. Wang RK, Jacques SL, Ma Z, Hurst S, Hanson SR, Gruber A. Three dimensional optical angiography. Opt Express. 2007;15(7):40834097. 8. Huang Y, Zhang Q, Thorell MR, et al. Swept-Source OCT Angiography of the Retinal Vasculature Using Intensity Differentiation-based Optical Microangiography Algorithms. Ophthalmic Surg Lasers Imaging Retina. 2014;1-8. 9. Bagci AM, Shahidi M, Ansari R, Blair M, Blair NP, Zelkha R. Thickness profiles of retinal layers by optical coherence tomography image segmentation. Am J Ophthalmol. 2008;146(5):679-687. 10. Tan PE, Yu PK, Balaratnasingam C, et al. Quantitative confocal imaging of the retinal microvasculature in the human retina. Invest Ophthalmol Vis Sci. 2012;53(9):5728-5736. 11. Sarraf D, Rahimy E, Fawzi AA, et al. Paracentral acute middle maculopathy: a new variant of acute macular neuroretinopathy associated with retinal capillary ischemia. JAMA Ophthalmol. 2013;131(10):1275-1287.
