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Spectral Domain Optical Coherence Tomography Angiography in Stargardt's Macular Dystrophy
Reports Spectral Domain Optical Coherence Tomography Angiography in Stargardt’s Macular Dystrophy Stargardt’s macular dystrophy (SMD) is the most common form of hereditary recessive macular dystrophy, seen in approximately 1 in 10 000 people, and accounts for 7% of all retinal degenerations.1 The pathophysiology is a well-described mutation in the ABCA4 gene, resulting in the accumulation of lipofuscin (modified residues of incompletely digested photoreceptor outer segments), retinal pigment epithelium (RPE) cell death, and irreversible progressive atrophy in the macula.2 Optical coherence tomography angiography (OCTA) is a unique imaging technique that provides high-resolution imaging of capillary networks and allows for segmentation of different layers of retinal and choroidal vasculature.3 We report 3 cases of SMD with distinct findings on OCTA that correlate with SMD pathology. Patients were imaged using an investigational OCTA prototype (Carl Zeiss Meditec, Dublin, CA) under Stanford University Institutional Review Board approval. Patients provided written consent for imaging and publication of OCT imaging. Analysis was performed using the built-in analysis software in the CIRRUS spectral domain (SD)-OCT 5000. Segmentation of vascular layers included the superficial retinal plexus, deep retinal plexus, avascular layer, choriocapillaris, and choroid. Standard imaging was obtained as indicated, including wide-field photography, autofluorescence, fluorescein angiography, and cross-sectional SD-OCT. Findings were compared with results from other multimodal imaging studies assessing SMD in the literature.
Advanced Stargardt’s Macular Dystrophy Case 1 was of a 40-year-old woman presenting with a bestcorrected visual acuity of 20/100 bilaterally. Intraocular pressures were within the normal range, the anterior segment examination was unremarkable, and the optic nerves seemed normal. Fundoscopy of the right eye showed central atrophy with pigment mottling and a few flecks; the left demonstrated an area of RPE atrophy. The patient underwent full-field electroretinography with normal results. Case 2 was of a 51-year-old woman presenting with a best-corrected visual acuity of 20/150 bilaterally. She had normal intraocular pressure. Fundoscopy demonstrated central geographic atrophy, attenuated vessels, and pigmentary mottling in the periphery in both eyes. Full-field electroretinography was normal. OCTA images were obtained at the level of the superior retina and choriocapillaris. There was notable central retinal thinning, with increased intercapillary space and foveal avascular zone remodeling seen at the level of the superficial retinal plexus in both patients (Fig 2, available at www.ophthalmologyretina.org). B-scans demonstrated photoreceptor loss and RPE atrophy. In the right eye of case 1, the choriocapillaris seemed to be atrophic centrally, with the area of atrophy involving the region of RPE Ó 2016 by the American Academy of Ophthalmology Published by Elsevier Inc.
loss. The area of photoreceptor loss appeared to extend further than the area of RPE atrophy (Fig 1AeD). There was a clear delineation of the area of RPE atrophy on OCTA in the left eye (Fig 1EeG), which corresponded with a dense area of geographic atrophy on autofluorescence, but with better visualization of the choriocapillaris vasculature. In this clearly demarcated area, there seemed to be a loss of vascular density at the level of the choriocapillaris. The surrounding macula had intact photoreceptor and RPE layers and a normal appearing choriocapillaris. In case 2, the choriocapillaris of both eyes had decreased vascular density that correlated with the region of RPE loss (Fig 1HeJ).
Early Stargardt’s Macular Dystrophy Case 3 was a 28-year-old man with a best-corrected visual acuity of 20/80 bilaterally and clear media. Fundoscopy revealed a dull and granular foveal center with irregular yellow flecks in both eyes. Autofluorescence imaging illustrated an atrophic zone surrounded by a ring of hyperfluoresence. Cross-sectional SD-OCT showed loss of foveal photoreceptors, a small ring of RPE loss, and an occasional fleck. Similar to cases 1 and 2, this subject had retinal thinning as well as foveal avascular zone remodeling. However, these changes seemed to be less pronounced and may represent an earlier stage of disease. Both eyes showed central loss of the photoreceptor layer, with patchy (but not complete) atrophy of the RPE. The RPE layer seemed to be somewhat intact at the fovea center. These changes corresponded with a central area of hyper fluorescence, which may represent normal vascular density centrally with a surrounding area of reduced vascular density at the level of the choriocapillaris on en face OCTA (right eye; Fig 1KeL). Pellegrini et al4 directly compared OCTA findings at the choriocapillaris with standard imaging techniques. They correlated the presence of dark atrophy with a surrounding ring seen on indocyanine green angiography, with severe loss of the choriocapillaris layer centrally, and a transition zone of reduced choriocapillaris vasculature surrounding this on OCTA.4 When en face OCTA images were correlated with B-scan findings in our study, it also suggested that loss of photoreceptors and RPE was a progressive process. Loss of photoreceptors could be seen covering the largest area spanning outward from the fovea center. This loss was followed by a smaller area of RPE layer loss. Loss of RPE correlated with reduced vascular density in the underlying choriocapillaris layer. This pattern implies that photoreceptor loss occurs before RPE atrophy and that loss of RPE occurs simultaneously with the destruction of the choriocapillaris layer. These findings differ from that described by de Carlo et al,5 who found that photoreceptor loss and RPE atrophy coincided well, and that the region of choriocapillaris changes was smaller than the photoreceptor and RPE changes.5 Furthermore, the third case in this series is a younger patient, earlier in the course of their disease. Findings of parafoveal RPE atrophy and choriocapillaris changes with central sparing suggest that the foveal center may be conserved in the initial stages of http://dx.doi.org/10.1016/j.oret.2016.12.008 ISSN 2468-6530/17
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Ophthalmology Retina Volume -, Number -, Month 2017
Figure 1. Case 1, right eye. A 6 6-mm optical coherence tomography angiography (OCTA) of the choriocapillaris (A), with corresponding B-scans (BeD) at the level indicated by the colored horizontal lines in A. The choriocapillaris appears intact at the level of the blue line in A and photoreceptor and retinal pigment epithelium (RPE) layers are intact on the corresponding B-scan (B). The hyperintense region of the choriocapillaris at this level of the yellow line in A correlates with loss of photoreceptor layer but intact RPE in C. Reduced vascular density is seen in the choriocapillaris at the level of the red line in A, which correlates with loss of both the photoreceptor layer and RPE layer in D. Case 1, left eye. A 6 6-mm OCTA of the choriocapillaris (E), with corresponding B-scan (F, G) at the level indicated by the colored horizontal lines in E. The choriocapillaris, photoreceptor layer and RPE are intact in F at the level of the purple line in E. In the clearly demarcated area in E there seems to be loss of vasculature at the level of the choriocapillaris. There is a clear delineation of the area of RPE atrophy on the B-scan (G) at this level (orange line in E). Case 2, right eye. A 6 6-mm OCTA of the choriocapillaris (H), with corresponding B-scans (I, J) at the level indicated by the colored horizontal blue lines in H. There is decreased vascular density of the choriocapillaris in H. The B-scan shows diffuse photoreceptor loss and RPE disruption (I) at the level of the green line in H. The RPE disruption correlates with the area of choriocapillaris atrophy. The intact choriocapillaris at the level of the pink line in H corresponds with the intact photoreceptor layer and RPE in J. Case 3, right eye A 6 6-mm OCTA of the choriocapillaris (K), with corresponding B-scan (L) at the level indicated by the cyan horizontal line in K. There is reduced vascular density of the choriocapillaris in the parafoveal region. The central area of hyperfluorescence represents normal vascular density of the choriocapillaris at the fovea center. The B-scan shows central loss of the photoreceptor layer, with patchy atrophy of the RPE. The RPE layer is intact at the fovea center.
SMD. We found characteristic findings of SMD at the level of the superficial retinal capillary plexus consistent with previous reports.5 Given the small number of cases described in these reports, it is difficult to determine conclusively the sequence of these events. Further investigation of this phenomenon with a larger sample size and objective measurements over time from the early stages of SMD to late progression may give further insight into the natural history of this disease. With the recent advances in gene therapy, this noninvasive technique in conjunction with
2
cross-sectional SD-OCT may be useful as a clinical and research tool in determining progression of SMD and response to treatment.
MICHELE LEE, MD GEORGIA KAIDONIS, MBBS, PHD THEODORE LENG, MD, MS Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, California
Reports Financial Disclosures: The authors have made the following disclosures: T.L.: Travel support e Zeiss; consultant e Valeant, Zeiss, Regeneron, Genentech, Alcon; grants e Genentech, Ohr, Allergan. Author Contributions: Conception and design: Leng Analysis and interpretation: Lee, Kaidonis Data collection: Lee, Kaidonis, Leng Correspondence: Theodore Leng, MD, MS, Byers Eye Institute at Stanford, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303. E-mail: [email protected].
2.
3.
4.
5. References 1. Rotenstreich Y, Fishman GA, Anderson RJ. Visual acuity loss and clinical observations in a large series of patients
with Stargardt disease. Ophthalmology. 2003;110: 1151e1158. Allikmets R, Singh N, Sun H, et al. A photoreceptor cellspecific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15: 236e246. Spaide RF, Klancnik Jr JM, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol. 2015;133: 45e50. Pellegrini M, Acquistapace A, Oldani M, et al. Dark atrophy: an optical coherence tomography angiography study. Ophthalmology. 2016;123:1879e1886. de Carlo TE, Adhi M, Salz DA, et al. Analysis of choroidal and retinal vasculature in inherited retinal degenerations using optical coherence tomography angiography. Ophthalmic Surg Lasers Imaging Retina. 2016;47: 120e127.
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Advanced Stargardt’s Macular Dystrophy Case 1 was of a 40-year-old woman presenting with a bestcorrected visual acuity of 20/100 bilaterally. Intraocular pressures were within the normal range, the anterior segment examination was unremarkable, and the optic nerves seemed normal. Fundoscopy of the right eye showed central atrophy with pigment mottling and a few flecks; the left demonstrated an area of RPE atrophy. The patient underwent full-field electroretinography with normal results. Case 2 was of a 51-year-old woman presenting with a best-corrected visual acuity of 20/150 bilaterally. She had normal intraocular pressure. Fundoscopy demonstrated central geographic atrophy, attenuated vessels, and pigmentary mottling in the periphery in both eyes. Full-field electroretinography was normal. OCTA images were obtained at the level of the superior retina and choriocapillaris. There was notable central retinal thinning, with increased intercapillary space and foveal avascular zone remodeling seen at the level of the superficial retinal plexus in both patients (Fig 2, available at www.ophthalmologyretina.org). B-scans demonstrated photoreceptor loss and RPE atrophy. In the right eye of case 1, the choriocapillaris seemed to be atrophic centrally, with the area of atrophy involving the region of RPE Ó 2016 by the American Academy of Ophthalmology Published by Elsevier Inc.
loss. The area of photoreceptor loss appeared to extend further than the area of RPE atrophy (Fig 1AeD). There was a clear delineation of the area of RPE atrophy on OCTA in the left eye (Fig 1EeG), which corresponded with a dense area of geographic atrophy on autofluorescence, but with better visualization of the choriocapillaris vasculature. In this clearly demarcated area, there seemed to be a loss of vascular density at the level of the choriocapillaris. The surrounding macula had intact photoreceptor and RPE layers and a normal appearing choriocapillaris. In case 2, the choriocapillaris of both eyes had decreased vascular density that correlated with the region of RPE loss (Fig 1HeJ).
Early Stargardt’s Macular Dystrophy Case 3 was a 28-year-old man with a best-corrected visual acuity of 20/80 bilaterally and clear media. Fundoscopy revealed a dull and granular foveal center with irregular yellow flecks in both eyes. Autofluorescence imaging illustrated an atrophic zone surrounded by a ring of hyperfluoresence. Cross-sectional SD-OCT showed loss of foveal photoreceptors, a small ring of RPE loss, and an occasional fleck. Similar to cases 1 and 2, this subject had retinal thinning as well as foveal avascular zone remodeling. However, these changes seemed to be less pronounced and may represent an earlier stage of disease. Both eyes showed central loss of the photoreceptor layer, with patchy (but not complete) atrophy of the RPE. The RPE layer seemed to be somewhat intact at the fovea center. These changes corresponded with a central area of hyper fluorescence, which may represent normal vascular density centrally with a surrounding area of reduced vascular density at the level of the choriocapillaris on en face OCTA (right eye; Fig 1KeL). Pellegrini et al4 directly compared OCTA findings at the choriocapillaris with standard imaging techniques. They correlated the presence of dark atrophy with a surrounding ring seen on indocyanine green angiography, with severe loss of the choriocapillaris layer centrally, and a transition zone of reduced choriocapillaris vasculature surrounding this on OCTA.4 When en face OCTA images were correlated with B-scan findings in our study, it also suggested that loss of photoreceptors and RPE was a progressive process. Loss of photoreceptors could be seen covering the largest area spanning outward from the fovea center. This loss was followed by a smaller area of RPE layer loss. Loss of RPE correlated with reduced vascular density in the underlying choriocapillaris layer. This pattern implies that photoreceptor loss occurs before RPE atrophy and that loss of RPE occurs simultaneously with the destruction of the choriocapillaris layer. These findings differ from that described by de Carlo et al,5 who found that photoreceptor loss and RPE atrophy coincided well, and that the region of choriocapillaris changes was smaller than the photoreceptor and RPE changes.5 Furthermore, the third case in this series is a younger patient, earlier in the course of their disease. Findings of parafoveal RPE atrophy and choriocapillaris changes with central sparing suggest that the foveal center may be conserved in the initial stages of http://dx.doi.org/10.1016/j.oret.2016.12.008 ISSN 2468-6530/17
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Ophthalmology Retina Volume -, Number -, Month 2017
Figure 1. Case 1, right eye. A 6 6-mm optical coherence tomography angiography (OCTA) of the choriocapillaris (A), with corresponding B-scans (BeD) at the level indicated by the colored horizontal lines in A. The choriocapillaris appears intact at the level of the blue line in A and photoreceptor and retinal pigment epithelium (RPE) layers are intact on the corresponding B-scan (B). The hyperintense region of the choriocapillaris at this level of the yellow line in A correlates with loss of photoreceptor layer but intact RPE in C. Reduced vascular density is seen in the choriocapillaris at the level of the red line in A, which correlates with loss of both the photoreceptor layer and RPE layer in D. Case 1, left eye. A 6 6-mm OCTA of the choriocapillaris (E), with corresponding B-scan (F, G) at the level indicated by the colored horizontal lines in E. The choriocapillaris, photoreceptor layer and RPE are intact in F at the level of the purple line in E. In the clearly demarcated area in E there seems to be loss of vasculature at the level of the choriocapillaris. There is a clear delineation of the area of RPE atrophy on the B-scan (G) at this level (orange line in E). Case 2, right eye. A 6 6-mm OCTA of the choriocapillaris (H), with corresponding B-scans (I, J) at the level indicated by the colored horizontal blue lines in H. There is decreased vascular density of the choriocapillaris in H. The B-scan shows diffuse photoreceptor loss and RPE disruption (I) at the level of the green line in H. The RPE disruption correlates with the area of choriocapillaris atrophy. The intact choriocapillaris at the level of the pink line in H corresponds with the intact photoreceptor layer and RPE in J. Case 3, right eye A 6 6-mm OCTA of the choriocapillaris (K), with corresponding B-scan (L) at the level indicated by the cyan horizontal line in K. There is reduced vascular density of the choriocapillaris in the parafoveal region. The central area of hyperfluorescence represents normal vascular density of the choriocapillaris at the fovea center. The B-scan shows central loss of the photoreceptor layer, with patchy atrophy of the RPE. The RPE layer is intact at the fovea center.
SMD. We found characteristic findings of SMD at the level of the superficial retinal capillary plexus consistent with previous reports.5 Given the small number of cases described in these reports, it is difficult to determine conclusively the sequence of these events. Further investigation of this phenomenon with a larger sample size and objective measurements over time from the early stages of SMD to late progression may give further insight into the natural history of this disease. With the recent advances in gene therapy, this noninvasive technique in conjunction with
2
cross-sectional SD-OCT may be useful as a clinical and research tool in determining progression of SMD and response to treatment.
MICHELE LEE, MD GEORGIA KAIDONIS, MBBS, PHD THEODORE LENG, MD, MS Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, California
Reports Financial Disclosures: The authors have made the following disclosures: T.L.: Travel support e Zeiss; consultant e Valeant, Zeiss, Regeneron, Genentech, Alcon; grants e Genentech, Ohr, Allergan. Author Contributions: Conception and design: Leng Analysis and interpretation: Lee, Kaidonis Data collection: Lee, Kaidonis, Leng Correspondence: Theodore Leng, MD, MS, Byers Eye Institute at Stanford, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303. E-mail: [email protected].
2.
3.
4.
5. References 1. Rotenstreich Y, Fishman GA, Anderson RJ. Visual acuity loss and clinical observations in a large series of patients
with Stargardt disease. Ophthalmology. 2003;110: 1151e1158. Allikmets R, Singh N, Sun H, et al. A photoreceptor cellspecific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15: 236e246. Spaide RF, Klancnik Jr JM, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol. 2015;133: 45e50. Pellegrini M, Acquistapace A, Oldani M, et al. Dark atrophy: an optical coherence tomography angiography study. Ophthalmology. 2016;123:1879e1886. de Carlo TE, Adhi M, Salz DA, et al. Analysis of choroidal and retinal vasculature in inherited retinal degenerations using optical coherence tomography angiography. Ophthalmic Surg Lasers Imaging Retina. 2016;47: 120e127.
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