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The Spectrum of Superficial and Deep Capillary Ischemia in Retinal Artery Occlusion
The Spectrum of Superficial and Deep Capillary Ischemia in Retinal Artery Occlusion SUQIN YU, CLAUDINE E. PANG, YUANYUAN GONG, K. BAILEY FREUND, LAWRENCE A. YANNUZZI, EHSAN RAHIMY, BRANDON J. LUJAN, HOMAYOUN TABANDEH, MICHAEL J. COONEY, AND DAVID SARRAF PURPOSE: To describe the spectrum of retinal capillary ischemia, including superficial and deep capillary ischemia, as identified with spectral-domain optical coherence tomography (SD OCT), that occurs in retinal arterial occlusive disease. DESIGN: Retrospective observational case series. METHODS: Clinical charts, color fundus photography, red-free fundus photography, fluorescein angiography, near-infrared reflectance, and SD OCT imaging in 40 eyes of 35 patients with retinal arterial occlusive disease were studied in both the acute and chronic phases in multicenter clinical practices. SD OCT imaging analysis was employed to characterize the presence of superficial and deep capillary ischemia in each eye. RESULTS: Of the 40 eyes, 15 eyes had central retinal artery occlusion (CRAO), 22 eyes had branch retinal artery occlusion (BRAO), and 3 eyes had cilioretinal artery occlusion. During the acute phase, SD OCT showed the following 3 distinct patterns, related to retinal ischemia occurring at varying levels within the retina: (1) thickening and hyperreflectivity of the inner retinal layers, including the nerve fiber and ganglion cell layers owing to ischemia of the superficial capillary plexus; (2) a hyperreflective band at the level of the inner nuclear layer, termed ‘‘paracentral acute middle maculopathy,’’ representing ischemia of the intermediate and deep retinal capillary plexuses (deep capillary ischemia); and (3) diffuse thickening and hyperreflectivity of both the inner and middle retinal layers, which represented both superficial and deep capillary ischemia. Of all eyes, 31 (78%)
Accepted for publication Sept 16, 2014. From the Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China (S.Y., Y.G.); Vitreous, Retina, Macula Consultants of New York, New York, New York (S.Y., C.E.P., K.B.F., L.A.Y., M.J.C.); LuEsther T. Mertz Retinal Research Center, Manhattan Eye Ear and Throat Hospital, New York, New York (C.E.P., K.B.F.); New York University School of Medicine, Department of Ophthalmology, New York, New York (K.B.F.); Columbia University School of Medicine, Department of Ophthalmology, New York, New York (L.A.Y.); Mid Atlantic Retina, The Retina Service of Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania (E.R.); West Coast Retina Medical Group, San Francisco, California (B.J.L.); Retina Vitreous Association Medical Group, Los Angeles, California (H.T.); Retinal Disorders and Ophthalmic Genetics Division, Jules Stein Eye Institute, University of California, Los Angeles, California (D.S.); and Greater Los Angeles VA Healthcare Center, Los Angeles, California (D.S.). Inquiries to David Sarraf, Retinal Disorders and Ophthalmic Genetics Division, Jules Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2014.09.027
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2015 BY
had both superficial and deep lesions. The remaining 9 eyes (22%) had isolated deep capillary ischemia producing paracentral acute middle maculopathy with sparing of the superficial capillary plexus and a normal fluorescein angiographic appearance. As the lesions evolved into the chronic phase over the ensuing 3 months, the resultant thinning and atrophy reflected the retinal layers affected during the acute phase. CONCLUSION: SD OCT imaging reveals the spectrum of capillary ischemia in retinal artery occlusive disease showing variable involvement of the superficial and intermediate/deep capillary plexuses. Isolated deep capillary ischemia manifested as paracentral acute middle maculopathy on SD OCT and may be seen in some eyes with retinal arterial circulation compromise despite complete absence of perfusion abnormalities on fluorescein angiography. (Am J Ophthalmol 2015;159:53–63. Ó 2015 by Elsevier Inc. All rights reserved.)
W
ITH THE ADVENT OF SPECTRAL-DOMAIN OPTI-
cal coherence tomography (SD OCT) imaging, retinal ischemia can be more precisely localized to the superficial and/or intermediate and deep retinal capillary plexuses.1 The superficial capillary plexus resides in the ganglion cell layer.1–6 Superficial capillary ischemia has been well defined in the literature and usually presents clinically as a fluffy ‘‘cotton-wool spot’’ in the acute phase7,8 and as a ‘‘retinal depression sign’’ in the chronic phase.9 The intermediate and deep capillary plexuses reside at the inner and outer border zone of the inner nuclear layer (INL), respectively. Ischemia of these plexuses, deep capillary ischemia, analogous to a deep ‘‘cotton-wool spot,’’ presents as a deeper gray-white lesion with defined edges in the acute phase and evolves into subtle darkening of the retina in the chronic phase.1 Fluorescein angiography (FA) has traditionally been the gold standard for evaluating retinal vascular circulation; however, standard FA cannot visualize the intermediate and deep capillary plexuses and therefore may fail to identify deep capillary ischemia.1,10,11 With SD OCT imaging, however, deep capillary ischemia in the acute phase can be recognized as a characteristic hyperreflective lesion at the level of the inner nuclear layer, referred to as paracentral acute middle maculopathy.10–12 Paracentral acute middle maculopathy has been described in association with acute macular neuroretinopathy,12,13 diabetic retinopathy,1 retinal
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RIGHTS RESERVED.
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vein occlusion,11 and various retinal vascular disorders.1,10 The purpose of this study is to characterize the spectrum of SD OCT findings of eyes with retinal artery occlusion and its association with paracentral acute middle maculopathy.
METHODS THIS STUDY WAS APPROVED BY THE VARIOUS INSTITU-
tional Review Boards affiliated with each author, and adhered to the tenets of the Declaration of Helsinki and was conducted in accordance with regulations set forth by the Health Insurance Portability and Accountability Act. This was a retrospective, nonconsecutive, observational case series, which included patients with the diagnosis of retinal artery occlusion based on clinical findings and ancillary testing, including ophthalmoscopic evidence of retinal whitening, delayed arterial filling with FA, and evidence of macular ischemia with SD OCT imaging. All patients underwent comprehensive ophthalmic assessment, including Snellen visual acuity, slit-lamp biomicroscopy, indirect ophthalmoscopy, color and red-free fundus photography, FA, and SD OCT analysis with simultaneous nearinfrared reflectance (NIR) imaging at a central wavelength of 820 nm (Spectralis, Heidelberg, Germany or Cirrus HDOCT; Carl Zeiss Meditec, Inc, Dublin, California, USA). Retinal arterial occlusive disease was categorized into central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), and cilioretinal artery occlusion based on color fundus photography and FA. The acute hyperreflective lesions on SD OCT imaging were classified into superficial or deep capillary ischemia according to the location and extent of involvement of the retinal layers. The proportion of eyes that displayed both superficial and deep capillary ischemia vs isolated superficial or deep capillary ischemia was analyzed. The lesions on SD OCT imaging were correlated with the clinical appearance and FA. Statistical analysis of the final visual acuities of patients with CRAO and BRAO were performed using SPSS Software Version 22.0 (IBM Corporation, Armonk, New York, USA), converting Snellen visual acuities to logarithm of the minimal angle of resolution (logMAR). The difference in the mean final visual acuity was calculated using independent sample t test, taking a value of less than .05 as statistically significant.
RESULTS A TOTAL OF 40 EYES OF 35 PATIENTS (15 MALE AND 20 FEMALE)
with retinal arterial occlusive disease, with a mean age of 61 6 17.8 years (range 17–91 years), were included in the study. The mean duration of follow-up was 20 6 26.2 months (range 0–120 months). Of the 40 eyes, 15 eyes had CRAO, 22 eyes had BRAO, and 3 eyes had cilioretinal 54
artery occlusion. Of all 40 eyes, 6 eyes with CRAO and 2 eyes with BRAO had preceding or concurrent central retinal vein occlusion (CRVO). Twenty-four out of 35 (70%) patients had preexisting systemic vascular disease, of which 17 out of 24 (70%) of these could be attributed to hypertension. A summary table showing the demographics and systemic diseases of all patients is included (Table). The acute phase of retinal arterial occlusive disease was studied in 35 eyes since 5 eyes presented at baseline in the chronic phase, while the chronic phase was studied in 38 eyes owing to lack of follow-up in 2 eyes. With SD OCT imaging, the acute phase showed 3 types of patterns, depending on the level of involvement of the retinal layers: (1) thickening and hyperreflectivity of the inner retinal layers, including the nerve fiber and ganglion cell layers, owing to ischemia of the superficial capillary plexus; (2) a hyperreflective band at the level of the inner nuclear layer, also termed paracentral acute middle maculopathy, that represented ischemia of the intermediate and deep retinal capillary plexuses; and (3) diffuse thickening and hyperreflectivity of both the inner and middle retinal layers, which represented ischemia of the superficial, intermediate, and deep capillary plexuses. These lesions could be found at varying locations throughout the posterior pole but were always paracentral and were also identified at varying phases throughout the course of the disease. The chronic phase was seen to occur between 1 and 3 months from the acute baseline presentation and showed resultant thinning and atrophy of the retinal layers, corresponding to the acute lesions, when present. Of note, intermediate and deep retinal capillary ischemia never occurred exclusive of the other; and therefore we refer to deep capillary ischemia to include both levels of involvement. Of all 40 eyes, 31 (78%) demonstrated evidence of superficial and deep capillary ischemia in the same eye as both independent and contiguous lesions. None of the eyes showed only superficial capillary ischemia in the absence of deep capillary ischemia. In 7 eyes with contiguous lesions, the core of the lesion demonstrated superficial and deep capillary ischemia while the border zone of retinal whitening in the perifoveal region showed deep capillary ischemia. Nine eyes (22%) showed only deep capillary ischemia, manifested as paracentral acute middle maculopathy on SD OCT. Isolated deep capillary ischemia could be seen in CRAO (n ¼ 4), BRAO (n ¼ 4), and cilioretinal artery occlusion (n ¼ 1) cases. FA failed to show any identifiable perfusion abnormality in 8 out of these 9 cases. The lesions with superficial capillary ischemia corresponded to areas of fluffy inner retinal whitening, similar to a cottonwool spot, and appeared hyporeflective with NIR imaging, although not as prominently dark as the deeper lesions. The paracentral acute middle maculopathy lesions clinically corresponded to areas of milder and deeper retinal whitening and were more prominently hyporeflective with NIR. In cases of isolated paracentral acute middle maculopathy and deep capillary ischemia, there was no evidence of
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TABLE. Summary Data of Patients With Retinal Artery Occlusion Patient No
Sex
Age
Eye
BCVA (Onset)
1 2 3
M F F
64 81 57
OS CF CF OS CF CF OS 20/150 20/50
4 5 6 7 8
M M F F F
91 63 57 64 80
9 10 11 12 13 14
F F F F M F
49 67 33 49 91 55
OD OD OS OD OS OD OD OD OD OD OS OS
CF 20/300 20/400 20/200 20/80 20/50 20/20 20/50 20/20 20/40 20/20 CF
NLP 20/300 20/400 20/200 20/40 20/30 20/30 20/50 20/30
15 16 17
F M F
67 82 80
18
F
70
OS OD OS OD OD
CF 20/80 CF 20/25 20/150
CF 20/60 CF 20/25 20/40
19
M
17
OD 20/15
20 21 22 23 24 25 26 27 28
F F M F M F M F M
59 87 80 45 77 81 63 55 42
29
M
39
30
F
26
OD OS OS OD OD OS OD OS OD OS OD OS OD
31
F
51
32 33 34 35
M M M M
55 67 58 44
20/20 20/50 CF HM HM 4/200 20/25 20/200 20/20 20/20 20/20 20/20 20/25
OD 20/20 20/200 OS 20/20 OS CF OD 20/400 OD CF
BCVA (Final)
Followup (Mo)
12 18 6
20/20 20/200 CF 20/400
Other Eye Diseases
SCI/DCI
CRAO CRAO CRAO
SCIþDCI SCIþDCI SCIþDCI CSC
120 8 9 7 24 24 44 4 46 0 0 0
CRAO CRAO CRAO Cilioretinal AO BRAO BRAO BRAO BRAO BRAO BRAO BRAO CRAO
SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI AMD Only DCI
3 4 49 49 50
BRAO BRAO CRVOþCRAO BRAO BRAO
SCIþDCI SCIþDCI SCIþDCI Only DCI SCIþDCI
BRAO
SCIþDCI
0 9 2 25 27 8 1 11 62 62 11 11 5
BRAO CRVOþCRAO CRVOþCRAO CRVOþCRAO CRVOþCRAO CRVOþBRAO CRVOþBRAO CRVOþCRAO BRAO BRAO BRAO BRAO BRAO
Only DCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI Only DCI
4 6 0 80 1 0
BRAO BRAO Cilioretinal AO Cilioretinal AO CRAO CRAO
Only DCI SCIþDCI RD, s/p PPV Only DCI Only DCI Macular hole Only DCI Only DCI
0
5/200 CF HM HM 4/200 20/25 20/100 20/20 20/20 20/20 20/20 20/25
Diagnosis
Systemic Diseases
HTN HTN Non Hodgkin lymphoma, DM, HTN, renal failure, aortic atheroscleros, sleep apnea, emphysema, anemia, DVT, sepsis HTN
HTN HTN, anemia SLE 320 years
HTN HTN, s/p aortic stent and bypass surgery Left carotid dissection, left parietal lobe embolic strokes DM, RHD POAG HTN, renal failure, stroke Ocular lymphoma, Multiple myeloma, non-Hodgkin radiotherapy lymphoma NPDR, HTN, DM, hypercholesterolemia, macroaneurysm arrhythmia/left bundle branch block, mild erythrocytosis and thrombocytosis 36 years Prepapillary vascular loop Aortic calcifications Rubeosis HTN, Parkinson disease Vasculitis VSD HTN POAG
Multiple myeloma, neuropathy
NPDR NPDR Vasculitis Vasculitis
DM
Factor V Leiden deficiency, hemophilia C, gastric bypass surgery SLE, MI HTN HTN, hyperlipidemia
AMD ¼ age-related macular degeneration; AO ¼ artery occlusion; BCVA ¼ best-corrected visual acuity; BRAO ¼ branch retinal artery occlusion; CF ¼ counting fingers; CRAO ¼ central retinal artery occlusion; CRVO ¼ central retinal vein occlusion; CSC ¼ central serous chorioretinopathy; DCI ¼ deep capillary ischemia; DM ¼ diabetes mellitus; DVT ¼ deep vein thrombosis; HTN ¼ hypertension; LP ¼ light perception; MI ¼ myocardial infarction; N/A ¼ not applicable; NPDR ¼ nonproliferating diabetic retinopathy; POAG ¼ primary open-angle glaucoma; PPV ¼ pars plana vitrectomy; RHD ¼ rheumatic heart disease; SCI¼ superficial capillary ischemia; SLE ¼ systemic lupus erythematosus; s/p ¼ status post; VSD ¼ ventricular septal defect.
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inner retinal involvement at any time by virtue of the absence of inner retinal hyperreflectivity and inner retinal thinning. In all 15 eyes with CRAO, SD OCT showed varying degrees of hyperreflectivity at the fovea corresponding to a cherry-red spot and attributable to increased transmission of light relative to the adjacent opacified perifoveal retina. The mean final visual acuity was counting fingers in eyes with CRAO and 20/40 in eyes with BRAO. In eyes with CRAO, the mean final visual acuity was equally poor in eyes with isolated deep capillary ischemia vs eyes with both superficial and deep capillary ischemia (P ¼ .77). Similarly, in eyes with BRAO, there was no difference in the mean final visual acuity in eyes with isolated deep capillary ischemia compared to eyes with both superficial and deep capillary ischemia (P ¼ .45). Here, we describe some representative cases to showcase the spectrum of SD OCT findings in retinal arterial occlusive disease. CASE 1:
An 80-year-old woman (Patient 8) with systemic hypertension and anemia presented with sudden vision loss and visual acuity of 20/80 in the left eye. Clinical examination showed BRAO with retinal whitening along the superotemporal arcade and FA showed delayed perfusion of the superotemporal branch retinal artery. Within the area of retinal whitening during the acute phase, SD OCT showed thickening and hyperreflectivity of both the inner and middle retinal layers, with sparing of the outer retinal architecture. In the chronic phase 2 years later, SD OCT through the same area showed thinning and atrophy of the inner and middle retinal layers. Immediately adjacent to this area at the edge of retinal whitening toward the fovea, SD OCT showed hyperreflectivity of the middle layers at the level of the INL consistent with paracentral acute middle maculopathy in the acute phase. In the chronic phase, SD OCT through this area demonstrated thinning of only the INL. FA in the chronic phase failed to reveal any evidence of ischemia or nonperfusion. In summary, this case of BRAO showed evidence of both superficial and deep capillary ischemia in 1 region and only deep capillary ischemia in a separate region of the macula. This case also clearly demonstrated that FA would fail to identify a BRAO in the chronic phase, whereas SD OCT may be more helpful in demonstrating evidence of previous retinal ischemia (Figure 1). CASE 2:
A 91-year-old man (Patient 13) with systemic hypertension and cardiovascular disease presented with sudden painless superior visual field loss in the left eye. Visual acuity was 20/20 at baseline despite the presence of nonexudative age-related macular degeneration. Clinical examination in the acute phase showed scattered areas of retinal whitening along the inferior branch retinal artery while FA demonstrated delayed perfusion in the inferior branch retinal artery consistent with an inferior BRAO. SD OCT imaging showed thickening and hyperreflectivity
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of the inner retinal layers adjacent to the optic nerve, consistent with superficial capillary ischemia, and a cotton-wool spot. Thickening and hyperreflectivity of both the inner and middle retinal layers at the level of the INL were noted temporally, indicating superficial and deep capillary ischemia (Figure 2). CASE 3:
A 59-year-old woman (Patient 20) with systemic hypertension and aortic calcification presented with a new paracentral scotoma in the right eye. Visual acuity was 20/ 20 and baseline clinical examination revealed an area of retinal whitening inferotemporal to the fovea associated with a proximal intravascular Hollenhorst embolus, consistent with acute BRAO. FA did not reveal any evidence of retinal nonperfusion; however, SD OCT through the area of retinal whitening showed thickening and hyperreflectivity of only the middle retinal layers at the level of the INL, consistent with paracentral acute middle maculopathy, indicating isolated deep capillary ischemia. This case highlights the importance of SD OCT imaging in the evaluation of retinal arterial occlusive disease, as FA was normal and failed to identify ischemia of the intermediate or deep capillary plexuses (Figure 3).
CASE 4:
A 64-year-old woman (Patient 7) with systemic hypertension presented with sudden painless vision loss and visual acuity of 20/200 in the right eye. Clinical examination revealed an area of retinal whitening involving the inferior macula just adjacent to the fovea, with a subtle ‘‘cherry-red spot’’ appearance. SD OCT imaging through separate areas of retinal whitening revealed paracentral acute middle maculopathy and deep capillary ischemia closest to the fovea and both superficial and deep capillary ischemia in the area of inferior retinal whitening. FA showed delayed perfusion of the cilioretinal artery. This case is an example of cilioretinal artery occlusion, with lesions demonstrating superficial and deep capillary ischemia and lesions with only deep capillary ischemia at different locations of the macula (Figure 4).
CASE 5: An 81-year-old woman (Patient 2) with systemic hypertension presented with sudden painless loss in vision and visual acuity of counting fingers in the left eye. Clinical examination revealed a CRAO with the characteristic ‘‘cherry-red spot’’ appearance. FA showed delayed vascular filling while SD OCT imaging in the acute phase revealed thickening and hyperreflectivity of the inner and middle retinal layers surrounding the fovea. This case illustrates an acute CRAO causing both superficial and deep capillary ischemia. Note the hyperreflective foveal region owing to increased transmission of light centrally (Figure 5). CASE 6: A 55-year-old woman (Patient 14) presented with acute central scotoma and counting fingers vision in the left eye. Clinical examination and FA were unremarkable, but SD OCT imaging revealed diffuse
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FIGURE 1. Case 1: Multimodal imaging of an 80-year-old woman (Patient 8) with branch retinal artery occlusion (BRAO) in the left eye (OS) showing both superficial and deep capillary ischemia and their evolution from the acute to chronic phase. (Top row, left) Color fundus photograph at the acute phase showing retinal whitening and opacity along the superotemporal branch artery. (Top row, second from left) Fluorescein angiography (FA) at the acute phase showing delayed perfusion of the superotemporal branch artery. (Top row, third from left) Color fundus photograph at the chronic phase showing resolution of the retinal whitening. (Top right) FA at the chronic phase showing no evidence of perfusion insufficiency. (Second row, left) Spectral-domain optical coherence tomography (SD OCT) in the acute phase through the ischemic area (green line in Top row, left image) showing thickening and hyperreflectivity of the inner and middle retinal layers owing to the presence of both superficial and deep capillary ischemia. (Second row, right) SD OCT in the chronic phase through the ischemic area (green line in Top row, third from left image) showing subsequent thinning of the inner and middle retinal layers. (Third row, left) SD OCT in the acute phase through the fovea, at the edge of the ischemic area (yellow line in Top row, left image), showing thickening and hyperreflectivity of the middle retinal layers (arrows) referred to as paracentral acute middle maculopathy, indicating deep capillary ischemia. (Third row, right) SD OCT in the chronic phase through the fovea, at the edge of the ischemic area (yellow line in Top row, third from left image) showing subsequent thinning of only the middle retinal layers (arrows). (Bottom row, left) High magnification of the deep capillary ischemia in the acute phase showing thickening and hyperreflectivity of the middle retinal layers (boxed in image above). (Bottom row, right) High magnification of the deep capillary ischemia in the chronic phase showing thinning of the middle retinal layers (boxed in image above).
hyperreflectivity in the middle retinal layers at the level of the INL or paracentral acute middle maculopathy in all areas surrounding the fovea. A CRAO causing paracentral acute middle maculopathy and associated with diffuse deep capillary ischemia was suspected, and systemic evaluation including magnetic resonance angiography identified the presence of carotid dissection. Note the hyperreflective quality of the foveal region owing to relative central increase in light transmission (Figure 6).
DISCUSSION IN THIS STUDY, THE PRESENCE OF BOTH SUPERFICIAL AND
deep capillary ischemia as either separate or continuous VOL. 159, NO. 1
lesions occurred in the great majority (78%) of eyes with various forms of retinal artery occlusion (eg, in Cases 1, 2, 4, and 5), while isolated deep capillary ischemia or paracentral acute middle maculopathy occurred in 22% of eyes (eg, in Cases 3 and 6). In all cases, the acute phase of macular ischemia was typically characterized by swelling and hyperreflectivity with SD OCT imaging and was followed by thinning of the involved layers in the chronic phase, consistent with findings in the literature.1,14,15 This study highlights the importance of SD OCT imaging as a diagnostic tool, since the FA alone—in particular during the chronic phase—may not show any evidence of perfusion abnormalities, as was demonstrated in Cases 1, 3 and 6. Paracentral acute middle maculopathy is a recently described SD OCT lesion defined by hyperreflectivity in
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FIGURE 2. Case 2: Multimodal imaging of a 91-year-old man (Patient 13) with a history of nonexudative age-related macular degeneration (AMD) and new-onset branch retinal artery occlusion (BRAO) in the left eye (OS), showing both superficial and deep capillary ischemia in the acute phase. (Top row) Color fundus photograph and spectral-domain optical coherence tomography (SD OCT) imaging taken 2 years prior to presentation showing normal retinal architecture except for a few drusen. (Second row, left) Color fundus photograph taken at presentation showing mild retinal whitening along the inferotemporal branch retinal artery consistent with a BRAO. (Second row, right) SD OCT imaging through the yellow line in the image on the left, showing an area of thickening and hyperreflectivity of the inner retinal layers at the area closer to the optic nerve (yellow arrow). There is a separate area located temporally that showed thickening and hyperreflectivity of both the inner and middle retinal layers (white arrow). (Bottom row, left) Fluorescein angiography showing delayed filling in the inferotemporal branch retinal artery. (Bottom row, right) SD OCT imaging through the yellow line in the image on the left, showing an area of superficial capillary ischemia (yellow arrow) and an area of superficial and deep capillary ischemia (white arrow).
the middle retinal layers at the level of the inner nuclear layer.12 Paracentral acute middle maculopathy has been reported in association with various retinal disorders, including CRVO and diabetic retinopathy,1,10–12 and may be attributable to ischemia of the intermediate and deep retinal capillary plexuses, anatomically located at the inner and outer zones of the INL, respectively. This study has shown that paracentral acute middle maculopathy may be variably identified in eyes with retinal arterial occlusive disease and its occurrence depended on the location and extent of the retinal arterial circulation compromise. Retinal arterial occlusive disease frequently caused lesions with both superficial and deep capillary ischemia, while other cases showed only deep capillary ischemia. With SD OCT, the ischemic lesions appeared thickened and hyperreflective in the acute phase and invariably evolved into thinning and atrophy of the respective retinal layers in the chronic phase (Figure 7). A prominent middle limiting membrane (p-MLM) sign, detected on SD OCT imaging, is a recently introduced term that refers to an inner retinal hyperreflective line at 58
the level of the outer plexiform layer.16 This is synonymous with paracentral acute middle maculopathy but fails to take into account the paracentral and placoid opacification that occurs at the inner nuclear and inner plexiform layers. Moreover, the p-MLM sign is variably present and fails to account for the etiologic mechanism of deep capillary ischemia.1,10–12 Hence, the terms paracentral acute middle maculopathy and deep capillary ischemia have been adopted throughout this study. This study presented several cases of CRAO and BRAO with clinical and angiographic evidence of arterial occlusion and associated superficial and deep capillary ischemia with SD OCT analysis. Cases of retinal arterial occlusion were also presented with isolated paracentral acute middle maculopathy and deep capillary ischemia. Some of these cases showed only subtle evidence of retinal artery occlusion, such as a faint cherry-red spot, while others were normal clinically and angiographically. Case 6, for example, did not show any clinical or angiographic evidence of CRAO, but SD OCT showed a diffuse paracentral acute middle maculopathy lesion and subsequent magnetic
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FIGURE 3. Case 3: Multimodal imaging of a 59-year-old woman (Patient 20) with a branch retinal artery occlusion in the right eye (OD) showing isolated deep capillary ischemia. (Top row, left) Color fundus photograph showing mild retinal whitening inferotemporal to the central fovea, consistent with a BRAO. (Top row, right) Fluorescein angiography (FA) was normal and showed no evidence of perfusion insufficiency. (Second row, left) Magnified color photograph showing a Hollenhorst plaque (arrow). (Second row, right) Magnified FA showing a subtle narrowing of the retinal vessel but no visible delay in filling. (Bottom) Spectral-domain optical coherence tomography showing thickening and hyperreflectivity of the middle layers and paracentral middle maculopathy (arrows).
resonance angiography identified carotid dissection. These cases of diffuse isolated paracentral acute middle maculopathy indicating widespread deep capillary ischemia are likely the result of a CRAO. The lack of angiographic compromise at the time of presentation may be the result of subsequent recanalization and reperfusion or vasospasm of the central retinal artery. However, one may argue that the diagnosis of CRAO may be unsubstantiated and that these cases should just be referred to as paracentral VOL. 159, NO. 1
acute middle maculopathy. Despite having only middle retinal layer involvement, patients with isolated diffuse paracentral acute middle maculopathy may suffer profound visual loss, consistent with CRAO. The presence of different levels of ischemia within the spectrum of retinal artery occlusion may be attributable to a variation in ischemic susceptibility. We propose that the deep capillary plexus may be more vulnerable to an ischemic insult, as it may reside in a watershed region of
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FIGURE 4. Case 4: Multimodal imaging of a 64-year-old woman (Patient 7) with cilioretinal artery occlusion in the right eye (OD) showing both superficial and deep capillary ischemia in the acute phase. (Left) Color fundus photograph showing mild retinal whitening along the cilioretinal artery. (Right, top row) Near-infrared reflectance (NIR) and corresponding spectral-domain optical coherence tomography (SD OCT) through an area superior to the fovea showing normal reflectance and normal retinal structures. (Right, middle row) NIR and corresponding SD OCT through the edge of ischemic whitening at the fovea showing a hyporeflective area on NIR corresponding to paracentral acute middle maculopathy lesion on SD OCT, representing deep capillary ischemia. (Right, bottom row) NIR and corresponding SD OCT through the center of retinal whitening inferior to the fovea showing the hyporeflective area on NIR corresponding to thickening and hyperreflectively of the inner and middle retinal layers on SD OCT, representing superficial and deep capillary ischemia.
FIGURE 5. Case 5: Multimodal imaging of an 81-year-old woman (Patient 2) with central retinal artery occlusion (CRAO) in the left eye (OS) showing both superficial and deep capillary ischemia in the acute phase. (Top row, left) Color fundus photograph showing the characteristic ‘‘cherry-red spot’’ appearance in acute CRAO. (Top row, right) Spectral-domain optical coherence tomography (SD OCT) through the fovea showing thickening and hyperreflectivity of the inner and middle retinal layers, indicating both superficial and deep capillary ischemia. There is a hyperreflective quality at the central fovea at the level of the outer retinal layers, retinal pigment epithelium, and choroid that may be related to a contrast effect elicited by transmission of incoming light at the fovea and relative blocking of incoming light by the paracentral ischemic lesions. (Bottom row) Sequential fluorescein angiography showing delayed filling in the retinal arterial circulation.
oxygen supply. Studies on intraretinal oxygen tension in cat and rat retinas have shown that there is a dip in the oxygen tension levels in the middle retinal layers (at the level of the INL) compared to the inner and outer retinal layers.17–19 Extrapolation to human eyes supports the presence of a watershed zone in the middle retinal layers, thereby explaining the presence of isolated paracentral acute 60
middle maculopathy in the absence of superficial capillary ischemia in the setting of retinal vasculopathy including retinal artery and vein occlusions.11 In addition, in eyes with contiguous superficial and deep capillary ischemia, paracentral acute middle maculopathy was found predominantly at the edges rather than at the core of ischemic lesions. Since there may be a greater ischemic insult at the
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FIGURE 6. Case 6: Multimodal imaging and carotid angiography of a 55-year-old woman (Patient 14) with carotid artery dissection and central retinal artery occlusion (CRAO) in the left eye (OS) showing isolated paracentral acute middle maculopathy in the acute phase. (Top row, left) Color fundus photograph was normal. (Top row, second from left) Fundus autofluorescence was normal. (Top row, third from left) Fluorescein angiography (FA) was normal. (Top row, right) FA in the late phase showing no evidence of perfusion insufficiency. (Second row) Near-infrared reflectance (NIR) and corresponding spectral-domain optical coherence tomography (SD OCT) through the fovea showing an area of hyporeflectance on NIR surrounding the fovea, corresponding to isolated paracentral acute middle maculopathy lesion on SD OCT. (Third row) Magnified view of the SD OCT showing isolated paracentral acute middle maculopathy surrounding the fovea, indicating isolated deep capillary ischemia. There is a hyperreflective quality at the central fovea related to the contrast effect brought about by transmission of incoming light at the fovea and relative blocking of incoming light by the paracentral acute middle maculopathy lesions. (Bottom row, left) Humphrey visual field test showing a normal visual field OD and a central scotoma OS corresponding to the central ischemic lesion. (Bottom row, right) Carotid angiography showing a carotid dissection on the left side.
core in the central distribution of the occluded artery than at the edges, owing to adjacent perfused vascular retina, this further supports our theory that the deep capillary plexus resides within the more vulnerable watershed zone and may be more susceptible to ischemia. Another plausible explanation for the appearance of paracentral acute middle maculopathy at the perifoveal region may be the physiological paucity of superficial capillaries in this area.20 In this study of retinal arterial occlusive disease, we identified cases with isolated paracentral acute middle VOL. 159, NO. 1
maculopathy but failed to note any cases with isolated superficial capillary ischemia. Isolated ‘‘cotton-wool spots’’ may represent a different mechanism or level of occlusion (ie, pre–capillary arteriolar occlusion or superficial capillary ischemia, as occurs with diabetic retinopathy).1 Our inability to identify isolated superficial capillary ischemia in association with retinal artery occlusion may be attributable to selection bias and/or to the limitations of a retrospective study. Other limitations of this study include the small sample size and nonconsecutive series in which the
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FIGURE 7. Summary of the spectrum of retinal capillary ischemic lesions seen with spectral-domain optical coherence tomography in retinal arterial occlusive disease in the acute and chronic phase.
prevalence of paracentral acute middle maculopathy cannot be accurately analyzed. Future prospective and larger consecutive case studies may be able to show that paracentral acute middle maculopathy occurs more or less frequently than noted in this study. More advanced technologies such as en face systems and OCT angiography may be able to better analyze and characterize abnormalities of the deep capillary plexus. In the cases of CRAO with paracentral acute middle maculopathy, with or without involvement of the inner retinal layers, we identified a characteristic hyperreflective quality of the central fovea. This interesting finding may be attributable to a contrast effect in which swelling and hyperreflectivity in the paracentral regions cause relative blocking of incoming light, while the incoming light at the central fovea is fully transmitted. This appearance may be
the SD OCT correlate of a cherry-red spot and may alert the clinician to search for evidence of superficial and deep capillary ischemia with SD OCT analysis (Figures 5 and 6). In conclusion, SD OCT imaging revealed the full spectrum of ischemic changes in retinal arterial occlusive disease, including superficial capillary ischemia when the inner retinal layers are involved and deep capillary ischemia or paracentral acute middle maculopathy when the middle retinal layers are involved. A combination of both was found to be most common in this study. SD OCT imaging may be capable of detecting paracentral acute middle maculopathy in cases where the FA is normal without any evidence of nonperfusion or ischemia and may be a more sensitive tool for evaluating retinal arterial occlusive disease and, more specifically, characterizing the nature and extent of macular ischemia.
THE AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Financial Disclosures: K. Bailey Freund: Consultant to Heidelberg Engineering, Regeneron, Genentech and Bayer HealthCare, and Thrombogenics. David Sarraf: Speaker for Heidelberg and receives grant support from Regeneron. Brandon Lujan: Consultant to Genentech/Roche, Regeneron, Avalanche. Lawrence A. Yannuzzi: Consultant to Genentech, Bayer, and Regeneron. Michael J. Cooney: Consultant to Bausch & Lomb; Speaker for Bausch & Lomb, Genentech, and Regeneron. The Macula Foundation, Inc, New York, New York will provide financial support in relation to printing of the publication and has no role in the design or conduct of this study. Contributions of authors: design of the study (S.Y., C.E.P., K.B.F., D.S.); conduct of the study (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); data collection (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); data management (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); data analysis (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); interpretation of data (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); preparation of manuscript (S.Y., C.E.P., K.B.F., D.S.); review of manuscript (S.Y., C.E.P., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); approval of manuscript (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.).
REFERENCES 1. Yu S, Wang F, Pang CE, et al. Multimodal imaging findings in retinal deep capillary ischemia. Retina 2014;34(4):636–646. 2. Dorrell MI, Friedlander M, Smith LEH. Chapter 2. Retinal vascular development. In: Joussen AM, Gardner TW,
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Kirchhof B, Ryan SJ, eds. Retinal Vascular Disease. Berlin, Heidelberg, New York: Springer-Verlag; 2007:29–30. 3. 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.
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4. Henkind P, Hansen RI, Szalay J. Ocular circulation. In: Records RE, ed. Physiology of the Human Eye and Visual System. Hagerstown, MD: Harper & Row; 1979:98–155. 5. Zhang HR. Scanning electron-microscopic study of corrosion casts on retinal and choroidal angioarchitecture in man and animals. Prog Retin Eye Res 1994;13(1):243–270. 6. Foreman DM, Bagley S, Moore J, et al. Three dimensional analysis of the retinal vasculature using immunofluorescent staining and confocal laser scanning microscopy. Br J Ophthalmol 1996;80(3):246–251. 7. Jampol LM. Arteriolar occlusive diseases of the macula. Ophthalmology 1983;90(5):534–539. 8. Schmidt D. The mystery of cotton-wool spots, a review of recent and historical descriptions. Eur J Med Res 2008; 13(6):231–266. 9. Goldbaum MH. Retinal depression sign indicating a small retinal infarct. Am J Ophthalmol 1978;86(1):45–55. 10. Rahimy E, Sarraf D. Paracentral acute middle maculopathy spectral-domain optical coherence tomography feature of deep capillary ischemia. Curr Opin Ophthalmol 2014;25(3):207–212. 11. Rahimy E, Sarraf D, Dollin ML, et al. Paracentral acute middle maculopathy in nonischemic central retinal vein occlusion. Am J Ophthalmol 2014;158(2):372–380. 12. 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.
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13. Tsui I, Sarraf D. Paracentral acute middle maculopathy and acute macular neuroretinopathy. Ophthalmic Surg Lasers Imaging Retina 2013;44(6):S33–35. 14. Chu YK, Hong YT, Byeon SH, Kwon OW. In vivo detection of acute ischemic damages in retinal arterial occlusion with optical coherence tomography: a ‘‘prominent middle limiting membrane sign.’’. Retina 2013;33(10):2110–2117. 15. Kim JS, Maheshwary AS, Bartsch DU, et al. The microperimetry of resolved cotton-wool spots in eyes of patients with hypertension and diabetes mellitus. Arch Ophthalmol 2011; 129(7):879–884. 16. Coady PA, Cunningham ET Jr, Vora RA, et al. Spectral domain optical coherence tomography findings in eyes with acute ischaemic retinal whitening. Br J Ophthalmol 2014; http://dx.doi.org/10.1136/bjophthalmol-2014-304900. 17. Lisenmeier RA. Effects of light and darkness on oxygen distribution and consumption in the cat retina. J Gen Physiol 1986; 88(4):521–542. 18. Cheng HY, Nair G, Walker TA, et al. Structural and functional MRI reveals multiple retinal layers. Proc Natl Acad Sci U S A 2006;103(46):17525–17530. 19. Yu DY, Cringle SJ, Alder V, Su EN. Intraretinal oxygen distribution in the rat with graded systemic hyperoxia and hypercapnia. Invest Ophthalmol Vis Sci 1999;40(9):2082–2087. 20. Iwasaki M, Inomata H. Relation between superficial capillaries and foveal structures in the human retina. Invest Ophthalmol Vis Sci 1986;27(12):1698–1705.
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Biosketch Suqin Yu, MD is a medical retina specialist. She received her medical degree from Shanghai Medical University and master degree from Shanghai Medical College of Fudan University. Dr Yu is currently an Associate Professor of the Department of Ophthalmology, Shanghai Jiaotong University affiliated Shanghai First People’s Hospital, China.
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Biosketch Dr Claudine E. Pang graduated with Distinction from the National University of Singapore, completed ophthalmology training with the Royal College of Surgeons in Edinburgh (FRSCEd) and College of Ophthalmologists, Academy of Medicine in Singapore (FAMS). She has received 2 vitreoretinal fellowships at the Vitreous Retina Macula Consultants of New York, Manhattan Eye, Ear and Throat Hospital, followed by the William H. Ross Vitreoretinal Surgical Fellowship at the University of British Columbia, Vancouver. Her interests are in macular diseases, vitreomacular surgery and retinal imaging.
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Accepted for publication Sept 16, 2014. From the Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China (S.Y., Y.G.); Vitreous, Retina, Macula Consultants of New York, New York, New York (S.Y., C.E.P., K.B.F., L.A.Y., M.J.C.); LuEsther T. Mertz Retinal Research Center, Manhattan Eye Ear and Throat Hospital, New York, New York (C.E.P., K.B.F.); New York University School of Medicine, Department of Ophthalmology, New York, New York (K.B.F.); Columbia University School of Medicine, Department of Ophthalmology, New York, New York (L.A.Y.); Mid Atlantic Retina, The Retina Service of Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania (E.R.); West Coast Retina Medical Group, San Francisco, California (B.J.L.); Retina Vitreous Association Medical Group, Los Angeles, California (H.T.); Retinal Disorders and Ophthalmic Genetics Division, Jules Stein Eye Institute, University of California, Los Angeles, California (D.S.); and Greater Los Angeles VA Healthcare Center, Los Angeles, California (D.S.). Inquiries to David Sarraf, Retinal Disorders and Ophthalmic Genetics Division, Jules Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2014.09.027
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2015 BY
had both superficial and deep lesions. The remaining 9 eyes (22%) had isolated deep capillary ischemia producing paracentral acute middle maculopathy with sparing of the superficial capillary plexus and a normal fluorescein angiographic appearance. As the lesions evolved into the chronic phase over the ensuing 3 months, the resultant thinning and atrophy reflected the retinal layers affected during the acute phase. CONCLUSION: SD OCT imaging reveals the spectrum of capillary ischemia in retinal artery occlusive disease showing variable involvement of the superficial and intermediate/deep capillary plexuses. Isolated deep capillary ischemia manifested as paracentral acute middle maculopathy on SD OCT and may be seen in some eyes with retinal arterial circulation compromise despite complete absence of perfusion abnormalities on fluorescein angiography. (Am J Ophthalmol 2015;159:53–63. Ó 2015 by Elsevier Inc. All rights reserved.)
W
ITH THE ADVENT OF SPECTRAL-DOMAIN OPTI-
cal coherence tomography (SD OCT) imaging, retinal ischemia can be more precisely localized to the superficial and/or intermediate and deep retinal capillary plexuses.1 The superficial capillary plexus resides in the ganglion cell layer.1–6 Superficial capillary ischemia has been well defined in the literature and usually presents clinically as a fluffy ‘‘cotton-wool spot’’ in the acute phase7,8 and as a ‘‘retinal depression sign’’ in the chronic phase.9 The intermediate and deep capillary plexuses reside at the inner and outer border zone of the inner nuclear layer (INL), respectively. Ischemia of these plexuses, deep capillary ischemia, analogous to a deep ‘‘cotton-wool spot,’’ presents as a deeper gray-white lesion with defined edges in the acute phase and evolves into subtle darkening of the retina in the chronic phase.1 Fluorescein angiography (FA) has traditionally been the gold standard for evaluating retinal vascular circulation; however, standard FA cannot visualize the intermediate and deep capillary plexuses and therefore may fail to identify deep capillary ischemia.1,10,11 With SD OCT imaging, however, deep capillary ischemia in the acute phase can be recognized as a characteristic hyperreflective lesion at the level of the inner nuclear layer, referred to as paracentral acute middle maculopathy.10–12 Paracentral acute middle maculopathy has been described in association with acute macular neuroretinopathy,12,13 diabetic retinopathy,1 retinal
ELSEVIER INC. ALL
RIGHTS RESERVED.
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vein occlusion,11 and various retinal vascular disorders.1,10 The purpose of this study is to characterize the spectrum of SD OCT findings of eyes with retinal artery occlusion and its association with paracentral acute middle maculopathy.
METHODS THIS STUDY WAS APPROVED BY THE VARIOUS INSTITU-
tional Review Boards affiliated with each author, and adhered to the tenets of the Declaration of Helsinki and was conducted in accordance with regulations set forth by the Health Insurance Portability and Accountability Act. This was a retrospective, nonconsecutive, observational case series, which included patients with the diagnosis of retinal artery occlusion based on clinical findings and ancillary testing, including ophthalmoscopic evidence of retinal whitening, delayed arterial filling with FA, and evidence of macular ischemia with SD OCT imaging. All patients underwent comprehensive ophthalmic assessment, including Snellen visual acuity, slit-lamp biomicroscopy, indirect ophthalmoscopy, color and red-free fundus photography, FA, and SD OCT analysis with simultaneous nearinfrared reflectance (NIR) imaging at a central wavelength of 820 nm (Spectralis, Heidelberg, Germany or Cirrus HDOCT; Carl Zeiss Meditec, Inc, Dublin, California, USA). Retinal arterial occlusive disease was categorized into central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), and cilioretinal artery occlusion based on color fundus photography and FA. The acute hyperreflective lesions on SD OCT imaging were classified into superficial or deep capillary ischemia according to the location and extent of involvement of the retinal layers. The proportion of eyes that displayed both superficial and deep capillary ischemia vs isolated superficial or deep capillary ischemia was analyzed. The lesions on SD OCT imaging were correlated with the clinical appearance and FA. Statistical analysis of the final visual acuities of patients with CRAO and BRAO were performed using SPSS Software Version 22.0 (IBM Corporation, Armonk, New York, USA), converting Snellen visual acuities to logarithm of the minimal angle of resolution (logMAR). The difference in the mean final visual acuity was calculated using independent sample t test, taking a value of less than .05 as statistically significant.
RESULTS A TOTAL OF 40 EYES OF 35 PATIENTS (15 MALE AND 20 FEMALE)
with retinal arterial occlusive disease, with a mean age of 61 6 17.8 years (range 17–91 years), were included in the study. The mean duration of follow-up was 20 6 26.2 months (range 0–120 months). Of the 40 eyes, 15 eyes had CRAO, 22 eyes had BRAO, and 3 eyes had cilioretinal 54
artery occlusion. Of all 40 eyes, 6 eyes with CRAO and 2 eyes with BRAO had preceding or concurrent central retinal vein occlusion (CRVO). Twenty-four out of 35 (70%) patients had preexisting systemic vascular disease, of which 17 out of 24 (70%) of these could be attributed to hypertension. A summary table showing the demographics and systemic diseases of all patients is included (Table). The acute phase of retinal arterial occlusive disease was studied in 35 eyes since 5 eyes presented at baseline in the chronic phase, while the chronic phase was studied in 38 eyes owing to lack of follow-up in 2 eyes. With SD OCT imaging, the acute phase showed 3 types of patterns, depending on the level of involvement of the retinal layers: (1) thickening and hyperreflectivity of the inner retinal layers, including the nerve fiber and ganglion cell layers, owing to ischemia of the superficial capillary plexus; (2) a hyperreflective band at the level of the inner nuclear layer, also termed paracentral acute middle maculopathy, that represented ischemia of the intermediate and deep retinal capillary plexuses; and (3) diffuse thickening and hyperreflectivity of both the inner and middle retinal layers, which represented ischemia of the superficial, intermediate, and deep capillary plexuses. These lesions could be found at varying locations throughout the posterior pole but were always paracentral and were also identified at varying phases throughout the course of the disease. The chronic phase was seen to occur between 1 and 3 months from the acute baseline presentation and showed resultant thinning and atrophy of the retinal layers, corresponding to the acute lesions, when present. Of note, intermediate and deep retinal capillary ischemia never occurred exclusive of the other; and therefore we refer to deep capillary ischemia to include both levels of involvement. Of all 40 eyes, 31 (78%) demonstrated evidence of superficial and deep capillary ischemia in the same eye as both independent and contiguous lesions. None of the eyes showed only superficial capillary ischemia in the absence of deep capillary ischemia. In 7 eyes with contiguous lesions, the core of the lesion demonstrated superficial and deep capillary ischemia while the border zone of retinal whitening in the perifoveal region showed deep capillary ischemia. Nine eyes (22%) showed only deep capillary ischemia, manifested as paracentral acute middle maculopathy on SD OCT. Isolated deep capillary ischemia could be seen in CRAO (n ¼ 4), BRAO (n ¼ 4), and cilioretinal artery occlusion (n ¼ 1) cases. FA failed to show any identifiable perfusion abnormality in 8 out of these 9 cases. The lesions with superficial capillary ischemia corresponded to areas of fluffy inner retinal whitening, similar to a cottonwool spot, and appeared hyporeflective with NIR imaging, although not as prominently dark as the deeper lesions. The paracentral acute middle maculopathy lesions clinically corresponded to areas of milder and deeper retinal whitening and were more prominently hyporeflective with NIR. In cases of isolated paracentral acute middle maculopathy and deep capillary ischemia, there was no evidence of
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TABLE. Summary Data of Patients With Retinal Artery Occlusion Patient No
Sex
Age
Eye
BCVA (Onset)
1 2 3
M F F
64 81 57
OS CF CF OS CF CF OS 20/150 20/50
4 5 6 7 8
M M F F F
91 63 57 64 80
9 10 11 12 13 14
F F F F M F
49 67 33 49 91 55
OD OD OS OD OS OD OD OD OD OD OS OS
CF 20/300 20/400 20/200 20/80 20/50 20/20 20/50 20/20 20/40 20/20 CF
NLP 20/300 20/400 20/200 20/40 20/30 20/30 20/50 20/30
15 16 17
F M F
67 82 80
18
F
70
OS OD OS OD OD
CF 20/80 CF 20/25 20/150
CF 20/60 CF 20/25 20/40
19
M
17
OD 20/15
20 21 22 23 24 25 26 27 28
F F M F M F M F M
59 87 80 45 77 81 63 55 42
29
M
39
30
F
26
OD OS OS OD OD OS OD OS OD OS OD OS OD
31
F
51
32 33 34 35
M M M M
55 67 58 44
20/20 20/50 CF HM HM 4/200 20/25 20/200 20/20 20/20 20/20 20/20 20/25
OD 20/20 20/200 OS 20/20 OS CF OD 20/400 OD CF
BCVA (Final)
Followup (Mo)
12 18 6
20/20 20/200 CF 20/400
Other Eye Diseases
SCI/DCI
CRAO CRAO CRAO
SCIþDCI SCIþDCI SCIþDCI CSC
120 8 9 7 24 24 44 4 46 0 0 0
CRAO CRAO CRAO Cilioretinal AO BRAO BRAO BRAO BRAO BRAO BRAO BRAO CRAO
SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI AMD Only DCI
3 4 49 49 50
BRAO BRAO CRVOþCRAO BRAO BRAO
SCIþDCI SCIþDCI SCIþDCI Only DCI SCIþDCI
BRAO
SCIþDCI
0 9 2 25 27 8 1 11 62 62 11 11 5
BRAO CRVOþCRAO CRVOþCRAO CRVOþCRAO CRVOþCRAO CRVOþBRAO CRVOþBRAO CRVOþCRAO BRAO BRAO BRAO BRAO BRAO
Only DCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI SCIþDCI Only DCI
4 6 0 80 1 0
BRAO BRAO Cilioretinal AO Cilioretinal AO CRAO CRAO
Only DCI SCIþDCI RD, s/p PPV Only DCI Only DCI Macular hole Only DCI Only DCI
0
5/200 CF HM HM 4/200 20/25 20/100 20/20 20/20 20/20 20/20 20/25
Diagnosis
Systemic Diseases
HTN HTN Non Hodgkin lymphoma, DM, HTN, renal failure, aortic atheroscleros, sleep apnea, emphysema, anemia, DVT, sepsis HTN
HTN HTN, anemia SLE 320 years
HTN HTN, s/p aortic stent and bypass surgery Left carotid dissection, left parietal lobe embolic strokes DM, RHD POAG HTN, renal failure, stroke Ocular lymphoma, Multiple myeloma, non-Hodgkin radiotherapy lymphoma NPDR, HTN, DM, hypercholesterolemia, macroaneurysm arrhythmia/left bundle branch block, mild erythrocytosis and thrombocytosis 36 years Prepapillary vascular loop Aortic calcifications Rubeosis HTN, Parkinson disease Vasculitis VSD HTN POAG
Multiple myeloma, neuropathy
NPDR NPDR Vasculitis Vasculitis
DM
Factor V Leiden deficiency, hemophilia C, gastric bypass surgery SLE, MI HTN HTN, hyperlipidemia
AMD ¼ age-related macular degeneration; AO ¼ artery occlusion; BCVA ¼ best-corrected visual acuity; BRAO ¼ branch retinal artery occlusion; CF ¼ counting fingers; CRAO ¼ central retinal artery occlusion; CRVO ¼ central retinal vein occlusion; CSC ¼ central serous chorioretinopathy; DCI ¼ deep capillary ischemia; DM ¼ diabetes mellitus; DVT ¼ deep vein thrombosis; HTN ¼ hypertension; LP ¼ light perception; MI ¼ myocardial infarction; N/A ¼ not applicable; NPDR ¼ nonproliferating diabetic retinopathy; POAG ¼ primary open-angle glaucoma; PPV ¼ pars plana vitrectomy; RHD ¼ rheumatic heart disease; SCI¼ superficial capillary ischemia; SLE ¼ systemic lupus erythematosus; s/p ¼ status post; VSD ¼ ventricular septal defect.
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inner retinal involvement at any time by virtue of the absence of inner retinal hyperreflectivity and inner retinal thinning. In all 15 eyes with CRAO, SD OCT showed varying degrees of hyperreflectivity at the fovea corresponding to a cherry-red spot and attributable to increased transmission of light relative to the adjacent opacified perifoveal retina. The mean final visual acuity was counting fingers in eyes with CRAO and 20/40 in eyes with BRAO. In eyes with CRAO, the mean final visual acuity was equally poor in eyes with isolated deep capillary ischemia vs eyes with both superficial and deep capillary ischemia (P ¼ .77). Similarly, in eyes with BRAO, there was no difference in the mean final visual acuity in eyes with isolated deep capillary ischemia compared to eyes with both superficial and deep capillary ischemia (P ¼ .45). Here, we describe some representative cases to showcase the spectrum of SD OCT findings in retinal arterial occlusive disease. CASE 1:
An 80-year-old woman (Patient 8) with systemic hypertension and anemia presented with sudden vision loss and visual acuity of 20/80 in the left eye. Clinical examination showed BRAO with retinal whitening along the superotemporal arcade and FA showed delayed perfusion of the superotemporal branch retinal artery. Within the area of retinal whitening during the acute phase, SD OCT showed thickening and hyperreflectivity of both the inner and middle retinal layers, with sparing of the outer retinal architecture. In the chronic phase 2 years later, SD OCT through the same area showed thinning and atrophy of the inner and middle retinal layers. Immediately adjacent to this area at the edge of retinal whitening toward the fovea, SD OCT showed hyperreflectivity of the middle layers at the level of the INL consistent with paracentral acute middle maculopathy in the acute phase. In the chronic phase, SD OCT through this area demonstrated thinning of only the INL. FA in the chronic phase failed to reveal any evidence of ischemia or nonperfusion. In summary, this case of BRAO showed evidence of both superficial and deep capillary ischemia in 1 region and only deep capillary ischemia in a separate region of the macula. This case also clearly demonstrated that FA would fail to identify a BRAO in the chronic phase, whereas SD OCT may be more helpful in demonstrating evidence of previous retinal ischemia (Figure 1). CASE 2:
A 91-year-old man (Patient 13) with systemic hypertension and cardiovascular disease presented with sudden painless superior visual field loss in the left eye. Visual acuity was 20/20 at baseline despite the presence of nonexudative age-related macular degeneration. Clinical examination in the acute phase showed scattered areas of retinal whitening along the inferior branch retinal artery while FA demonstrated delayed perfusion in the inferior branch retinal artery consistent with an inferior BRAO. SD OCT imaging showed thickening and hyperreflectivity
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of the inner retinal layers adjacent to the optic nerve, consistent with superficial capillary ischemia, and a cotton-wool spot. Thickening and hyperreflectivity of both the inner and middle retinal layers at the level of the INL were noted temporally, indicating superficial and deep capillary ischemia (Figure 2). CASE 3:
A 59-year-old woman (Patient 20) with systemic hypertension and aortic calcification presented with a new paracentral scotoma in the right eye. Visual acuity was 20/ 20 and baseline clinical examination revealed an area of retinal whitening inferotemporal to the fovea associated with a proximal intravascular Hollenhorst embolus, consistent with acute BRAO. FA did not reveal any evidence of retinal nonperfusion; however, SD OCT through the area of retinal whitening showed thickening and hyperreflectivity of only the middle retinal layers at the level of the INL, consistent with paracentral acute middle maculopathy, indicating isolated deep capillary ischemia. This case highlights the importance of SD OCT imaging in the evaluation of retinal arterial occlusive disease, as FA was normal and failed to identify ischemia of the intermediate or deep capillary plexuses (Figure 3).
CASE 4:
A 64-year-old woman (Patient 7) with systemic hypertension presented with sudden painless vision loss and visual acuity of 20/200 in the right eye. Clinical examination revealed an area of retinal whitening involving the inferior macula just adjacent to the fovea, with a subtle ‘‘cherry-red spot’’ appearance. SD OCT imaging through separate areas of retinal whitening revealed paracentral acute middle maculopathy and deep capillary ischemia closest to the fovea and both superficial and deep capillary ischemia in the area of inferior retinal whitening. FA showed delayed perfusion of the cilioretinal artery. This case is an example of cilioretinal artery occlusion, with lesions demonstrating superficial and deep capillary ischemia and lesions with only deep capillary ischemia at different locations of the macula (Figure 4).
CASE 5: An 81-year-old woman (Patient 2) with systemic hypertension presented with sudden painless loss in vision and visual acuity of counting fingers in the left eye. Clinical examination revealed a CRAO with the characteristic ‘‘cherry-red spot’’ appearance. FA showed delayed vascular filling while SD OCT imaging in the acute phase revealed thickening and hyperreflectivity of the inner and middle retinal layers surrounding the fovea. This case illustrates an acute CRAO causing both superficial and deep capillary ischemia. Note the hyperreflective foveal region owing to increased transmission of light centrally (Figure 5). CASE 6: A 55-year-old woman (Patient 14) presented with acute central scotoma and counting fingers vision in the left eye. Clinical examination and FA were unremarkable, but SD OCT imaging revealed diffuse
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FIGURE 1. Case 1: Multimodal imaging of an 80-year-old woman (Patient 8) with branch retinal artery occlusion (BRAO) in the left eye (OS) showing both superficial and deep capillary ischemia and their evolution from the acute to chronic phase. (Top row, left) Color fundus photograph at the acute phase showing retinal whitening and opacity along the superotemporal branch artery. (Top row, second from left) Fluorescein angiography (FA) at the acute phase showing delayed perfusion of the superotemporal branch artery. (Top row, third from left) Color fundus photograph at the chronic phase showing resolution of the retinal whitening. (Top right) FA at the chronic phase showing no evidence of perfusion insufficiency. (Second row, left) Spectral-domain optical coherence tomography (SD OCT) in the acute phase through the ischemic area (green line in Top row, left image) showing thickening and hyperreflectivity of the inner and middle retinal layers owing to the presence of both superficial and deep capillary ischemia. (Second row, right) SD OCT in the chronic phase through the ischemic area (green line in Top row, third from left image) showing subsequent thinning of the inner and middle retinal layers. (Third row, left) SD OCT in the acute phase through the fovea, at the edge of the ischemic area (yellow line in Top row, left image), showing thickening and hyperreflectivity of the middle retinal layers (arrows) referred to as paracentral acute middle maculopathy, indicating deep capillary ischemia. (Third row, right) SD OCT in the chronic phase through the fovea, at the edge of the ischemic area (yellow line in Top row, third from left image) showing subsequent thinning of only the middle retinal layers (arrows). (Bottom row, left) High magnification of the deep capillary ischemia in the acute phase showing thickening and hyperreflectivity of the middle retinal layers (boxed in image above). (Bottom row, right) High magnification of the deep capillary ischemia in the chronic phase showing thinning of the middle retinal layers (boxed in image above).
hyperreflectivity in the middle retinal layers at the level of the INL or paracentral acute middle maculopathy in all areas surrounding the fovea. A CRAO causing paracentral acute middle maculopathy and associated with diffuse deep capillary ischemia was suspected, and systemic evaluation including magnetic resonance angiography identified the presence of carotid dissection. Note the hyperreflective quality of the foveal region owing to relative central increase in light transmission (Figure 6).
DISCUSSION IN THIS STUDY, THE PRESENCE OF BOTH SUPERFICIAL AND
deep capillary ischemia as either separate or continuous VOL. 159, NO. 1
lesions occurred in the great majority (78%) of eyes with various forms of retinal artery occlusion (eg, in Cases 1, 2, 4, and 5), while isolated deep capillary ischemia or paracentral acute middle maculopathy occurred in 22% of eyes (eg, in Cases 3 and 6). In all cases, the acute phase of macular ischemia was typically characterized by swelling and hyperreflectivity with SD OCT imaging and was followed by thinning of the involved layers in the chronic phase, consistent with findings in the literature.1,14,15 This study highlights the importance of SD OCT imaging as a diagnostic tool, since the FA alone—in particular during the chronic phase—may not show any evidence of perfusion abnormalities, as was demonstrated in Cases 1, 3 and 6. Paracentral acute middle maculopathy is a recently described SD OCT lesion defined by hyperreflectivity in
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FIGURE 2. Case 2: Multimodal imaging of a 91-year-old man (Patient 13) with a history of nonexudative age-related macular degeneration (AMD) and new-onset branch retinal artery occlusion (BRAO) in the left eye (OS), showing both superficial and deep capillary ischemia in the acute phase. (Top row) Color fundus photograph and spectral-domain optical coherence tomography (SD OCT) imaging taken 2 years prior to presentation showing normal retinal architecture except for a few drusen. (Second row, left) Color fundus photograph taken at presentation showing mild retinal whitening along the inferotemporal branch retinal artery consistent with a BRAO. (Second row, right) SD OCT imaging through the yellow line in the image on the left, showing an area of thickening and hyperreflectivity of the inner retinal layers at the area closer to the optic nerve (yellow arrow). There is a separate area located temporally that showed thickening and hyperreflectivity of both the inner and middle retinal layers (white arrow). (Bottom row, left) Fluorescein angiography showing delayed filling in the inferotemporal branch retinal artery. (Bottom row, right) SD OCT imaging through the yellow line in the image on the left, showing an area of superficial capillary ischemia (yellow arrow) and an area of superficial and deep capillary ischemia (white arrow).
the middle retinal layers at the level of the inner nuclear layer.12 Paracentral acute middle maculopathy has been reported in association with various retinal disorders, including CRVO and diabetic retinopathy,1,10–12 and may be attributable to ischemia of the intermediate and deep retinal capillary plexuses, anatomically located at the inner and outer zones of the INL, respectively. This study has shown that paracentral acute middle maculopathy may be variably identified in eyes with retinal arterial occlusive disease and its occurrence depended on the location and extent of the retinal arterial circulation compromise. Retinal arterial occlusive disease frequently caused lesions with both superficial and deep capillary ischemia, while other cases showed only deep capillary ischemia. With SD OCT, the ischemic lesions appeared thickened and hyperreflective in the acute phase and invariably evolved into thinning and atrophy of the respective retinal layers in the chronic phase (Figure 7). A prominent middle limiting membrane (p-MLM) sign, detected on SD OCT imaging, is a recently introduced term that refers to an inner retinal hyperreflective line at 58
the level of the outer plexiform layer.16 This is synonymous with paracentral acute middle maculopathy but fails to take into account the paracentral and placoid opacification that occurs at the inner nuclear and inner plexiform layers. Moreover, the p-MLM sign is variably present and fails to account for the etiologic mechanism of deep capillary ischemia.1,10–12 Hence, the terms paracentral acute middle maculopathy and deep capillary ischemia have been adopted throughout this study. This study presented several cases of CRAO and BRAO with clinical and angiographic evidence of arterial occlusion and associated superficial and deep capillary ischemia with SD OCT analysis. Cases of retinal arterial occlusion were also presented with isolated paracentral acute middle maculopathy and deep capillary ischemia. Some of these cases showed only subtle evidence of retinal artery occlusion, such as a faint cherry-red spot, while others were normal clinically and angiographically. Case 6, for example, did not show any clinical or angiographic evidence of CRAO, but SD OCT showed a diffuse paracentral acute middle maculopathy lesion and subsequent magnetic
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FIGURE 3. Case 3: Multimodal imaging of a 59-year-old woman (Patient 20) with a branch retinal artery occlusion in the right eye (OD) showing isolated deep capillary ischemia. (Top row, left) Color fundus photograph showing mild retinal whitening inferotemporal to the central fovea, consistent with a BRAO. (Top row, right) Fluorescein angiography (FA) was normal and showed no evidence of perfusion insufficiency. (Second row, left) Magnified color photograph showing a Hollenhorst plaque (arrow). (Second row, right) Magnified FA showing a subtle narrowing of the retinal vessel but no visible delay in filling. (Bottom) Spectral-domain optical coherence tomography showing thickening and hyperreflectivity of the middle layers and paracentral middle maculopathy (arrows).
resonance angiography identified carotid dissection. These cases of diffuse isolated paracentral acute middle maculopathy indicating widespread deep capillary ischemia are likely the result of a CRAO. The lack of angiographic compromise at the time of presentation may be the result of subsequent recanalization and reperfusion or vasospasm of the central retinal artery. However, one may argue that the diagnosis of CRAO may be unsubstantiated and that these cases should just be referred to as paracentral VOL. 159, NO. 1
acute middle maculopathy. Despite having only middle retinal layer involvement, patients with isolated diffuse paracentral acute middle maculopathy may suffer profound visual loss, consistent with CRAO. The presence of different levels of ischemia within the spectrum of retinal artery occlusion may be attributable to a variation in ischemic susceptibility. We propose that the deep capillary plexus may be more vulnerable to an ischemic insult, as it may reside in a watershed region of
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FIGURE 4. Case 4: Multimodal imaging of a 64-year-old woman (Patient 7) with cilioretinal artery occlusion in the right eye (OD) showing both superficial and deep capillary ischemia in the acute phase. (Left) Color fundus photograph showing mild retinal whitening along the cilioretinal artery. (Right, top row) Near-infrared reflectance (NIR) and corresponding spectral-domain optical coherence tomography (SD OCT) through an area superior to the fovea showing normal reflectance and normal retinal structures. (Right, middle row) NIR and corresponding SD OCT through the edge of ischemic whitening at the fovea showing a hyporeflective area on NIR corresponding to paracentral acute middle maculopathy lesion on SD OCT, representing deep capillary ischemia. (Right, bottom row) NIR and corresponding SD OCT through the center of retinal whitening inferior to the fovea showing the hyporeflective area on NIR corresponding to thickening and hyperreflectively of the inner and middle retinal layers on SD OCT, representing superficial and deep capillary ischemia.
FIGURE 5. Case 5: Multimodal imaging of an 81-year-old woman (Patient 2) with central retinal artery occlusion (CRAO) in the left eye (OS) showing both superficial and deep capillary ischemia in the acute phase. (Top row, left) Color fundus photograph showing the characteristic ‘‘cherry-red spot’’ appearance in acute CRAO. (Top row, right) Spectral-domain optical coherence tomography (SD OCT) through the fovea showing thickening and hyperreflectivity of the inner and middle retinal layers, indicating both superficial and deep capillary ischemia. There is a hyperreflective quality at the central fovea at the level of the outer retinal layers, retinal pigment epithelium, and choroid that may be related to a contrast effect elicited by transmission of incoming light at the fovea and relative blocking of incoming light by the paracentral ischemic lesions. (Bottom row) Sequential fluorescein angiography showing delayed filling in the retinal arterial circulation.
oxygen supply. Studies on intraretinal oxygen tension in cat and rat retinas have shown that there is a dip in the oxygen tension levels in the middle retinal layers (at the level of the INL) compared to the inner and outer retinal layers.17–19 Extrapolation to human eyes supports the presence of a watershed zone in the middle retinal layers, thereby explaining the presence of isolated paracentral acute 60
middle maculopathy in the absence of superficial capillary ischemia in the setting of retinal vasculopathy including retinal artery and vein occlusions.11 In addition, in eyes with contiguous superficial and deep capillary ischemia, paracentral acute middle maculopathy was found predominantly at the edges rather than at the core of ischemic lesions. Since there may be a greater ischemic insult at the
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FIGURE 6. Case 6: Multimodal imaging and carotid angiography of a 55-year-old woman (Patient 14) with carotid artery dissection and central retinal artery occlusion (CRAO) in the left eye (OS) showing isolated paracentral acute middle maculopathy in the acute phase. (Top row, left) Color fundus photograph was normal. (Top row, second from left) Fundus autofluorescence was normal. (Top row, third from left) Fluorescein angiography (FA) was normal. (Top row, right) FA in the late phase showing no evidence of perfusion insufficiency. (Second row) Near-infrared reflectance (NIR) and corresponding spectral-domain optical coherence tomography (SD OCT) through the fovea showing an area of hyporeflectance on NIR surrounding the fovea, corresponding to isolated paracentral acute middle maculopathy lesion on SD OCT. (Third row) Magnified view of the SD OCT showing isolated paracentral acute middle maculopathy surrounding the fovea, indicating isolated deep capillary ischemia. There is a hyperreflective quality at the central fovea related to the contrast effect brought about by transmission of incoming light at the fovea and relative blocking of incoming light by the paracentral acute middle maculopathy lesions. (Bottom row, left) Humphrey visual field test showing a normal visual field OD and a central scotoma OS corresponding to the central ischemic lesion. (Bottom row, right) Carotid angiography showing a carotid dissection on the left side.
core in the central distribution of the occluded artery than at the edges, owing to adjacent perfused vascular retina, this further supports our theory that the deep capillary plexus resides within the more vulnerable watershed zone and may be more susceptible to ischemia. Another plausible explanation for the appearance of paracentral acute middle maculopathy at the perifoveal region may be the physiological paucity of superficial capillaries in this area.20 In this study of retinal arterial occlusive disease, we identified cases with isolated paracentral acute middle VOL. 159, NO. 1
maculopathy but failed to note any cases with isolated superficial capillary ischemia. Isolated ‘‘cotton-wool spots’’ may represent a different mechanism or level of occlusion (ie, pre–capillary arteriolar occlusion or superficial capillary ischemia, as occurs with diabetic retinopathy).1 Our inability to identify isolated superficial capillary ischemia in association with retinal artery occlusion may be attributable to selection bias and/or to the limitations of a retrospective study. Other limitations of this study include the small sample size and nonconsecutive series in which the
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FIGURE 7. Summary of the spectrum of retinal capillary ischemic lesions seen with spectral-domain optical coherence tomography in retinal arterial occlusive disease in the acute and chronic phase.
prevalence of paracentral acute middle maculopathy cannot be accurately analyzed. Future prospective and larger consecutive case studies may be able to show that paracentral acute middle maculopathy occurs more or less frequently than noted in this study. More advanced technologies such as en face systems and OCT angiography may be able to better analyze and characterize abnormalities of the deep capillary plexus. In the cases of CRAO with paracentral acute middle maculopathy, with or without involvement of the inner retinal layers, we identified a characteristic hyperreflective quality of the central fovea. This interesting finding may be attributable to a contrast effect in which swelling and hyperreflectivity in the paracentral regions cause relative blocking of incoming light, while the incoming light at the central fovea is fully transmitted. This appearance may be
the SD OCT correlate of a cherry-red spot and may alert the clinician to search for evidence of superficial and deep capillary ischemia with SD OCT analysis (Figures 5 and 6). In conclusion, SD OCT imaging revealed the full spectrum of ischemic changes in retinal arterial occlusive disease, including superficial capillary ischemia when the inner retinal layers are involved and deep capillary ischemia or paracentral acute middle maculopathy when the middle retinal layers are involved. A combination of both was found to be most common in this study. SD OCT imaging may be capable of detecting paracentral acute middle maculopathy in cases where the FA is normal without any evidence of nonperfusion or ischemia and may be a more sensitive tool for evaluating retinal arterial occlusive disease and, more specifically, characterizing the nature and extent of macular ischemia.
THE AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Financial Disclosures: K. Bailey Freund: Consultant to Heidelberg Engineering, Regeneron, Genentech and Bayer HealthCare, and Thrombogenics. David Sarraf: Speaker for Heidelberg and receives grant support from Regeneron. Brandon Lujan: Consultant to Genentech/Roche, Regeneron, Avalanche. Lawrence A. Yannuzzi: Consultant to Genentech, Bayer, and Regeneron. Michael J. Cooney: Consultant to Bausch & Lomb; Speaker for Bausch & Lomb, Genentech, and Regeneron. The Macula Foundation, Inc, New York, New York will provide financial support in relation to printing of the publication and has no role in the design or conduct of this study. Contributions of authors: design of the study (S.Y., C.E.P., K.B.F., D.S.); conduct of the study (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); data collection (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); data management (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); data analysis (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); interpretation of data (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); preparation of manuscript (S.Y., C.E.P., K.B.F., D.S.); review of manuscript (S.Y., C.E.P., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.); approval of manuscript (S.Y., C.E.P., Y.G., K.B.F., L.A.Y., E.R., B.J.L., H.T., M.J.C., D.S.).
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13. Tsui I, Sarraf D. Paracentral acute middle maculopathy and acute macular neuroretinopathy. Ophthalmic Surg Lasers Imaging Retina 2013;44(6):S33–35. 14. Chu YK, Hong YT, Byeon SH, Kwon OW. In vivo detection of acute ischemic damages in retinal arterial occlusion with optical coherence tomography: a ‘‘prominent middle limiting membrane sign.’’. Retina 2013;33(10):2110–2117. 15. Kim JS, Maheshwary AS, Bartsch DU, et al. The microperimetry of resolved cotton-wool spots in eyes of patients with hypertension and diabetes mellitus. Arch Ophthalmol 2011; 129(7):879–884. 16. Coady PA, Cunningham ET Jr, Vora RA, et al. Spectral domain optical coherence tomography findings in eyes with acute ischaemic retinal whitening. Br J Ophthalmol 2014; http://dx.doi.org/10.1136/bjophthalmol-2014-304900. 17. Lisenmeier RA. Effects of light and darkness on oxygen distribution and consumption in the cat retina. J Gen Physiol 1986; 88(4):521–542. 18. Cheng HY, Nair G, Walker TA, et al. Structural and functional MRI reveals multiple retinal layers. Proc Natl Acad Sci U S A 2006;103(46):17525–17530. 19. Yu DY, Cringle SJ, Alder V, Su EN. Intraretinal oxygen distribution in the rat with graded systemic hyperoxia and hypercapnia. Invest Ophthalmol Vis Sci 1999;40(9):2082–2087. 20. Iwasaki M, Inomata H. Relation between superficial capillaries and foveal structures in the human retina. Invest Ophthalmol Vis Sci 1986;27(12):1698–1705.
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Biosketch Suqin Yu, MD is a medical retina specialist. She received her medical degree from Shanghai Medical University and master degree from Shanghai Medical College of Fudan University. Dr Yu is currently an Associate Professor of the Department of Ophthalmology, Shanghai Jiaotong University affiliated Shanghai First People’s Hospital, China.
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Biosketch Dr Claudine E. Pang graduated with Distinction from the National University of Singapore, completed ophthalmology training with the Royal College of Surgeons in Edinburgh (FRSCEd) and College of Ophthalmologists, Academy of Medicine in Singapore (FAMS). She has received 2 vitreoretinal fellowships at the Vitreous Retina Macula Consultants of New York, Manhattan Eye, Ear and Throat Hospital, followed by the William H. Ross Vitreoretinal Surgical Fellowship at the University of British Columbia, Vancouver. Her interests are in macular diseases, vitreomacular surgery and retinal imaging.
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