Am J Ophthalmol 2014 Yu

The Spectrum of Superficial and Deep Capillary Ischemiain 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, ANDDAVID SARRAF

! PURPOSE: To describe the spectrum of retinal capillaryischemia, including superficial and deep capillaryischemia, as identified with spectral-domain opticalcoherence tomography (SD OCT), that occurs in retinalarterial 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 40eyes of 35 patients with retinal arterial occlusive diseasewere studied in both the acute and chronic phases inmulticenter clinical practices. SD OCT imaging analysiswas employed to characterize the presence of superficialand deep capillary ischemia in each eye.! RESULTS: Of the 40 eyes, 15 eyes had central retinalartery occlusion (CRAO), 22 eyes had branch retinal ar-tery occlusion (BRAO), and 3 eyes had cilioretinal arteryocclusion. During the acute phase, SD OCT showed thefollowing 3 distinct patterns, related to retinal ischemiaoccurring at varying levels within the retina: (1) thick-ening and hyperreflectivity of the inner retinal layers,including the nerve fiber and ganglion cell layers owingto ischemia of the superficial capillary plexus; (2) a hyper-reflective band at the level of the inner nuclear layer,termed ‘‘paracentral acute middle maculopathy,’’ repre-senting ischemia of the intermediate and deep retinalcapillary plexuses (deep capillary ischemia); and (3)diffuse thickening and hyperreflectivity of both the innerand middle retinal layers, which represented both super-ficial and deep capillary ischemia. Of all eyes, 31 (78%)

had both superficial and deep lesions. The remaining 9eyes (22%) had isolated deep capillary ischemia produc-ing paracentral acute middle maculopathy with sparingof the superficial capillary plexus and a normal fluoresceinangiographic appearance. As the lesions evolved into thechronic phase over the ensuing 3 months, the resultantthinning and atrophy reflected the retinal layers affectedduring the acute phase.! CONCLUSION: SD OCT imaging reveals the spectrumof capillary ischemia in retinal artery occlusive diseaseshowing variable involvement of the superficial and inter-mediate/deep capillary plexuses. Isolated deep capillaryischemia manifested as paracentral acute middle maculop-athy on SD OCT and may be seen in some eyes withretinal arterial circulation compromise despite completeabsence of perfusion abnormalities on fluoresceinangiography. (Am J Ophthalmol 2015;159:53–63.! 2015 by Elsevier Inc. All rights reserved.)

W ITH THE ADVENT OF SPECTRAL-DOMAIN OPTI-

cal coherence tomography (SDOCT) imaging,retinal ischemia can bemore precisely localized

to the superficial and/or intermediate and deep retinalcapillary plexuses.1 The superficial capillary plexus residesin the ganglion cell layer.1–6 Superficial capillaryischemia has been well defined in the literature andusually presents clinically as a fluffy ‘‘cotton-wool spot’’ inthe acute phase7,8 and as a ‘‘retinal depression sign’’ inthe chronic phase.9 The intermediate and deep capillaryplexuses reside at the inner and outer border zone of the in-ner nuclear layer (INL), respectively. Ischemia of theseplexuses, deep capillary ischemia, analogous to a deep ‘‘cot-ton-wool spot,’’ presents as a deeper gray-white lesion withdefined edges in the acute phase and evolves into subtledarkening of the retina in the chronic phase.1

Fluorescein angiography (FA) has traditionally been thegold standard for evaluating retinal vascular circulation; how-ever, standard FAcannot visualize the intermediate and deepcapillary plexuses and therefore may fail to identify deepcapillary ischemia.1,10,11 With SD OCT imaging, however,deep capillary ischemia in the acute phase can berecognized as a characteristic hyperreflective lesion at thelevel of the inner nuclear layer, referred to as paracentralacute middle maculopathy.10–12 Paracentral acute middlemaculopathy has been described in association with acutemacular neuroretinopathy,12,13 diabetic retinopathy,1 retinal

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 ResearchCenter, Manhattan Eye Ear and Throat Hospital, New York, New York(C.E.P., K.B.F.); New York University School of Medicine, Departmentof Ophthalmology, New York, New York (K.B.F.); Columbia UniversitySchool of Medicine, Department of Ophthalmology, New York, NewYork (L.A.Y.); Mid Atlantic Retina, The Retina Service of Wills EyeHospital, 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, LosAngeles, California (D.S.).

Inquiries to David Sarraf, Retinal Disorders and Ophthalmic GeneticsDivision, Jules Stein Eye Institute, University of California, Los Angeles,100 Stein Plaza, Los Angeles, CA 90095; e-mail: [email protected]

0002-9394/$36.00http://dx.doi.org/10.1016/j.ajo.2014.09.027

53! 2015 BY ELSEVIER INC. ALL RIGHTS RESERVED.

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http://dx.doi.org/10.1016/j.ajo.2014.09.027

vein occlusion,11 and various retinal vascular disorders.1,10

The purpose of this study is to characterize the spectrum ofSD OCT findings of eyes with retinal artery occlusion andits association with paracentral acute middle maculopathy.

METHODS

THIS STUDY WAS APPROVED BY THE VARIOUS INSTITU-

tional Review Boards affiliated with each author, andadhered to the tenets of the Declaration of Helsinki andwas conducted in accordance with regulations set forth bythe Health Insurance Portability and Accountability Act.

This was a retrospective, nonconsecutive, observationalcase series, which included patients with the diagnosis ofretinal artery occlusion based on clinical findings and ancil-lary testing, including ophthalmoscopic evidence of retinalwhitening, delayed arterial filling with FA, and evidence ofmacular ischemia with SD OCT imaging. All patients un-derwent comprehensive ophthalmic assessment, includingSnellen visual acuity, slit-lamp biomicroscopy, indirectophthalmoscopy, color and red-free fundus photography,FA, and SD OCT analysis with simultaneous near-infrared reflectance (NIR) imaging at a central wavelengthof 820 nm (Spectralis, Heidelberg, Germany or Cirrus HD-OCT; Carl Zeiss Meditec, Inc, Dublin, California, USA).Retinal arterial occlusive disease was categorized into cen-tral retinal artery occlusion (CRAO), branch retinal arteryocclusion (BRAO), and cilioretinal artery occlusion basedon color fundus photography and FA. The acute hyperre-flective lesions on SD OCT imaging were classified into su-perficial or deep capillary ischemia according to thelocation and extent of involvement of the retinal layers.The proportion of eyes that displayed both superficial anddeep capillary ischemia vs isolated superficial or deep capil-lary ischemia was analyzed. The lesions on SD OCT imag-ing were correlated with the clinical appearance and FA.

Statistical analysis of the final visual acuities of patientswith CRAO and BRAO were performed using SPSS Soft-ware Version 22.0 (IBM Corporation, Armonk, New York,USA), converting Snellen visual acuities to logarithm ofthe minimal angle of resolution (logMAR). The differencein the mean final visual acuity was calculated using inde-pendent sample t test, taking a value of less than .05 as sta-tistically significant.

RESULTS

ATOTALOF 40 EYESOF 35 PATIENTS (15MALEAND20 FEMALE)

with retinal arterial occlusive disease, with a mean age of 616 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 hadCRAO, 22 eyes had BRAO, and 3 eyes had cilioretinal

artery occlusion. Of all 40 eyes, 6 eyes with CRAO and 2eyeswithBRAOhadprecedingor concurrent central retinalvein occlusion (CRVO). Twenty-four out of 35 (70%) pa-tients had preexisting systemic vascular disease, of which17 out of 24 (70%) of these could be attributed to hyperten-sion. A summary table showing the demographics and sys-temic 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 thechronic phase, while the chronic phase was studied in 38eyes owing to lack of follow-up in 2 eyes. With SD OCTimaging, 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 retinallayers, including the nerve fiber and ganglion cell layers,owing to ischemia of the superficial capillary plexus; (2) ahyperreflective band at the level of the inner nuclear layer,also termed paracentral acute middle maculopathy, thatrepresented ischemia of the intermediate and deep retinalcapillary plexuses; and (3) diffuse thickening and hyperre-flectivity of both the inner and middle retinal layers, whichrepresented ischemia of the superficial, intermediate, anddeep capillary plexuses. These lesions could be found atvarying locations throughout the posterior pole but were al-ways paracentral and were also identified at varying phasesthroughout the course of the disease. The chronic phasewas seen to occur between 1 and 3 months from the acutebaseline presentation and showed resultant thinning andatrophy of the retinal layers, corresponding to the acute le-sions, when present. Of note, intermediate and deep retinalcapillary ischemia never occurred exclusive of the other;and therefore we refer to deep capillary ischemia to includeboth levels of involvement.Of all 40 eyes, 31 (78%) demonstrated evidence of super-

ficial and deep capillary ischemia in the same eye as bothindependent and contiguous lesions. None of the eyesshowed only superficial capillary ischemia in the absenceof deep capillary ischemia. In 7 eyes with contiguous le-sions, the core of the lesion demonstrated superficial anddeep capillary ischemia while the border zone of retinalwhitening in the perifoveal region showed deep capillaryischemia. Nine eyes (22%) showed only deep capillaryischemia, manifested as paracentral acute middle maculop-athy on SDOCT. Isolated deep capillary ischemia could beseen in CRAO (n¼ 4), BRAO (n¼ 4), and cilioretinal ar-tery occlusion (n¼ 1) cases. FA failed to show any identifi-able perfusion abnormality in 8 out of these 9 cases. Thelesions with superficial capillary ischemia corresponded toareas of fluffy inner retinal whitening, similar to a cotton-wool spot, and appeared hyporeflective with NIR imaging,although not as prominently dark as the deeper lesions. Theparacentral acute middle maculopathy lesions clinicallycorresponded to areas of milder and deeper retinal whit-ening and were more prominently hyporeflective withNIR. In cases of isolated paracentral acute middle maculop-athy and deep capillary ischemia, there was no evidence of

54 JANUARY 2015AMERICAN JOURNAL OF OPHTHALMOLOGY

TABLE. Summary Data of Patients With Retinal Artery Occlusion

Patient

No Sex Age Eye

BCVA

(Onset)

BCVA

(Final)

Follow-

up (Mo) Diagnosis SCI/DCI

Other Eye

Diseases Systemic Diseases

1 M 64 OS CF CF 12 CRAO SCIþDCI HTN

2 F 81 OS CF CF 18 CRAO SCIþDCI HTN

3 F 57 OS 20/150 20/50 6 CRAO SCIþDCI CSC Non Hodgkin lymphoma, DM, HTN, renal

failure, aortic atheroscleros, sleep apnea,

emphysema, anemia, DVT, sepsis

4 M 91 OD CF NLP 120 CRAO SCIþDCI HTN

5 M 63 OD 20/300 20/300 8 CRAO SCIþDCI

6 F 57 OS 20/400 20/400 9 CRAO SCIþDCI

7 F 64 OD 20/200 20/200 7 Cilioretinal AO SCIþDCI HTN

8 F 80 OS 20/80 20/40 24 BRAO SCIþDCI HTN, anemia

OD 20/50 20/30 24 BRAO SCIþDCI

9 F 49 OD 20/20 20/30 44 BRAO SCIþDCI SLE 320 years

10 F 67 OD 20/50 20/50 4 BRAO SCIþDCI

11 F 33 OD 20/20 20/30 46 BRAO SCIþDCI

12 F 49 OD 20/40 0 BRAO SCIþDCI HTN

13 M 91 OS 20/20 0 BRAO SCIþDCI AMD HTN, s/p aortic stent and bypass surgery

14 F 55 OS CF 0 CRAO Only DCI Left carotid dissection, left

parietal lobe embolic strokes

15 F 67 OS CF CF 3 BRAO SCIþDCI DM, RHD

16 M 82 OD 20/80 20/60 4 BRAO SCIþDCI POAG HTN, renal failure, stroke

17 F 80 OS CF CF 49 CRVOþCRAO SCIþDCI Ocular lymphoma,

radiotherapy

Multiple myeloma, non-Hodgkin

lymphomaOD 20/25 20/25 49 BRAO Only DCI

18 F 70 OD 20/150 20/40 50 BRAO SCIþDCI NPDR,

macroaneurysm

HTN, DM, hypercholesterolemia,

arrhythmia/left bundle branch

block, mild erythrocytosis and

thrombocytosis 36 years

19 M 17 OD 20/15 0 BRAO SCIþDCI Prepapillary

vascular loop

20 F 59 OD 20/20 0 BRAO Only DCI Aortic calcifications

21 F 87 OS 20/50 5/200 9 CRVOþCRAO SCIþDCI Rubeosis

22 M 80 OS CF CF 2 CRVOþCRAO SCIþDCI HTN, Parkinson disease

23 F 45 OD HM HM 25 CRVOþCRAO SCIþDCI Vasculitis VSD

24 M 77 OD HM HM 27 CRVOþCRAO SCIþDCI HTN

25 F 81 OS 4/200 4/200 8 CRVOþBRAO SCIþDCI

26 M 63 OD 20/25 20/25 1 CRVOþBRAO SCIþDCI POAG Multiple myeloma, neuropathy

27 F 55 OS 20/200 20/100 11 CRVOþCRAO SCIþDCI

28 M 42 OD 20/20 20/20 62 BRAO SCIþDCI NPDR DM

OS 20/20 20/20 62 BRAO SCIþDCI NPDR

29 M 39 OD 20/20 20/20 11 BRAO SCIþDCI Vasculitis

OS 20/20 20/20 11 BRAO SCIþDCI Vasculitis

30 F 26 OD 20/25 20/25 5 BRAO Only DCI Factor V Leiden deficiency, hemophilia

C, gastric bypass surgery

31 F 51 OD 20/20 20/20 4 BRAO Only DCI SLE, MI

20/200 20/200 6 BRAO SCIþDCI RD, s/p PPV

32 M 55 OS 20/20 0 Cilioretinal AO Only DCI HTN

33 M 67 OS CF CF 80 Cilioretinal AO Only DCI Macular hole HTN, hyperlipidemia

34 M 58 OD 20/400 20/400 1 CRAO Only DCI

35 M 44 OD CF 0 CRAO Only DCI

AMD¼ age-related macular degeneration; AO¼ artery occlusion; BCVA¼ best-corrected visual acuity; BRAO¼ branch retinal artery occlusion;

CF¼ counting fingers;CRAO¼ central retinal artery occlusion;CRVO¼ central retinal vein occlusion;CSC¼ central serous chorioretinopathy;DCI¼deepcapillary ischemia;DM¼diabetesmellitus;DVT¼deepvein thrombosis;HTN¼hypertension; LP¼ lightperception;MI¼myocardial infarction;

N/A¼ not applicable; NPDR¼ nonproliferating diabetic retinopathy; POAG¼ primary open-angle glaucoma; PPV¼ pars plana vitrectomy; RHD¼rheumaticheartdisease;SCI¼ superficial capillary ischemia;SLE¼ systemic lupuserythematosus;s/p¼ statuspost;VSD¼ ventricular septaldefect.

VOL. 159, NO. 1 55THE SPECTRUM OF RETINAL ISCHEMIA IN RETINAL ARTERY OCCLUSION

inner retinal involvement at any time by virtue of theabsence of inner retinal hyperreflectivity and inner retinalthinning. In all 15 eyes with CRAO, SD OCT showedvarying degrees of hyperreflectivity at the fovea corre-sponding to a cherry-red spot and attributable to increasedtransmission of light relative to the adjacent opacified peri-foveal retina.

The mean final visual acuity was counting fingers in eyeswith CRAO and 20/40 in eyes with BRAO. In eyes withCRAO, the mean final visual acuity was equally poor ineyes with isolated deep capillary ischemia vs eyes withboth superficial and deep capillary ischemia (P ¼ .77).Similarly, in eyes with BRAO, there was no difference inthe mean final visual acuity in eyes with isolated deep capil-lary ischemia compared to eyes with both superficial anddeep capillary ischemia (P ¼ .45).

Here, we describe some representative cases to showcasethe spectrum of SD OCT findings in retinal arterial occlu-sive disease.

! CASE 1: An 80-year-old woman (Patient 8) with systemichypertension and anemia presented with sudden vision lossand visual acuity of 20/80 in the left eye. Clinical examina-tion showed BRAOwith retinal whitening along the super-otemporal arcade and FA showed delayed perfusion of thesuperotemporal branch retinal artery. Within the area ofretinal whitening during the acute phase, SD OCT showedthickening and hyperreflectivity of both the inner and mid-dle retinal layers, with sparing of the outer retinal architec-ture. In the chronic phase 2 years later, SDOCTthrough thesame area showed thinning and atrophy of the inner andmiddle retinal layers. Immediately adjacent to this area atthe edge of retinal whitening toward the fovea, SD OCTshowed hyperreflectivity of the middle layers at the levelof the INL consistent with paracentral acute middle macul-opathy in the acute phase. In the chronic phase, SD OCTthrough this area demonstrated thinning of only the INL.FA in the chronic phase failed to reveal any evidence ofischemia or nonperfusion. In summary, this case of BRAOshowed evidence of both superficial and deep capillaryischemia in 1 region and only deep capillary ischemia in aseparate region of the macula. This case also clearly demon-strated that FAwould fail to identify a BRAO in the chronicphase, whereas SD OCT may be more helpful in demon-strating evidence of previous retinal ischemia (Figure 1).

! CASE 2: A 91-year-old man (Patient 13) with systemichypertension and cardiovascular disease presented withsudden painless superior visual field loss in the left eye. Vi-sual acuity was 20/20 at baseline despite the presence ofnonexudative age-related macular degeneration. Clinicalexamination in the acute phase showed scattered areas ofretinal whitening along the inferior branch retinal arterywhile FA demonstrated delayed perfusion in the inferiorbranch retinal artery consistent with an inferior BRAO.SD OCT imaging showed thickening and hyperreflectivity

of the inner retinal layers adjacent to the optic nerve,consistent with superficial capillary ischemia, and acotton-wool spot. Thickening and hyperreflectivity ofboth the inner and middle retinal layers at the level ofthe INL were noted temporally, indicating superficial anddeep capillary ischemia (Figure 2).

! CASE3: A 59-year-old woman (Patient 20) with systemichypertension and aortic calcification presented with a newparacentral scotoma in the right eye. Visual acuity was 20/20 and baseline clinical examination revealed an area ofretinal whitening inferotemporal to the fovea associatedwith a proximal intravascular Hollenhorst embolus, consis-tent with acute BRAO. FA did not reveal any evidence ofretinal nonperfusion; however, SD OCT through the areaof retinal whitening showed thickening and hyperreflectiv-ity 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 high-lights the importance of SD OCT imaging in the evalua-tion of retinal arterial occlusive disease, as FA wasnormal and failed to identify ischemia of the intermediateor deep capillary plexuses (Figure 3).

! CASE 4: A 64-year-old woman (Patient 7) with systemichypertension presented with sudden painless vision lossand visual acuity of 20/200 in the right eye. Clinical exam-ination revealed an area of retinal whitening involving theinferior macula just adjacent to the fovea, with a subtle‘‘cherry-red spot’’ appearance. SD OCT imaging throughseparate areas of retinal whitening revealed paracentralacute middle maculopathy and deep capillary ischemiaclosest to the fovea and both superficial and deep capillaryischemia in the area of inferior retinal whitening. FAshowed delayed perfusion of the cilioretinal artery. Thiscase is an example of cilioretinal artery occlusion, with le-sions demonstrating superficial and deep capillary ischemiaand lesions with only deep capillary ischemia at differentlocations of the macula (Figure 4).

! CASE5: An 81-year-old woman (Patient 2) with systemichypertension presented with sudden painless loss in visionand visual acuity of counting fingers in the left eye. Clinicalexamination revealed a CRAO with the characteristic‘‘cherry-red spot’’ appearance. FA showed delayed vascularfilling while SD OCT imaging in the acute phase revealedthickening and hyperreflectivity of the inner and middleretinal layers surrounding the fovea. This case illustratesan acute CRAO causing both superficial and deep capillaryischemia. Note the hyperreflective foveal region owing toincreased transmission of light centrally (Figure 5).

! CASE 6: A 55-year-old woman (Patient 14) presentedwith acute central scotoma and counting fingers visionin the left eye. Clinical examination and FA were unr-emarkable, but SD OCT imaging revealed diffuse


hyperreflectivity in the middle retinal layers at the level ofthe INL or paracentral acute middle maculopathy in allareas surrounding the fovea. A CRAO causing paracentralacute middle maculopathy and associated with diffuse deepcapillary ischemia was suspected, and systemic evaluationincluding magnetic resonance angiography identified thepresence of carotid dissection. Note the hyperreflectivequality of the foveal region owing to relative central in-crease in light transmission (Figure 6).

DISCUSSION

IN THIS STUDY, THE PRESENCE OF BOTH SUPERFICIAL AND

deep capillary ischemia as either separate or continuous

lesions occurred in the great majority (78%) of eyes withvarious forms of retinal artery occlusion (eg, in Cases 1, 2,4, and 5), while isolated deep capillary ischemia or paracen-tral acute middle maculopathy occurred in 22% of eyes (eg,in Cases 3 and 6). In all cases, the acute phase of macularischemia was typically characterized by swelling and hyper-reflectivitywith SDOCT imaging andwas followedby thin-ning of the involved layers in the chronic phase, consistentwith findings in the literature.1,14,15 This study highlightsthe importance of SD OCT imaging as a diagnostic tool,since the FA alone—in particular during the chronicphase—may not show any evidence of perfusionabnormalities, as was demonstrated in Cases 1, 3 and 6.Paracentral acute middle maculopathy is a recently

described SD OCT lesion defined by hyperreflectivity in

FIGURE1. Case 1:Multimodal imaging of an 80-year-old woman (Patient 8) with branch retinal artery occlusion (BRAO) in the lefteye (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) FAat the chronic phase showing no evidence of perfusion insufficiency. (Second row, left) Spectral-domain optical coherence tomogra-phy (SD OCT) in the acute phase through the ischemic area (green line in Top row, left image) showing thickening and hyperreflec-tivity of the inner and middle retinal layers owing to the presence of both superficial and deep capillary ischemia. (Second row, right)SDOCT in the chronic phase through the ischemic area (green line in Top row, third from left image) showing subsequent thinning ofthe 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 para-central acute middle maculopathy, indicating deep capillary ischemia. (Third row, right) SD OCT in the chronic phase through thefovea, at the edge of the ischemic area (yellow line in Top row, third from left image) showing subsequent thinning of only the middleretinal layers (arrows). (Bottom row, left) High magnification of the deep capillary ischemia in the acute phase showing thickeningand hyperreflectivity of the middle retinal layers (boxed in image above). (Bottom row, right) High magnification of the deep capillaryischemia in the chronic phase showing thinning of the middle retinal layers (boxed in image above).


the middle retinal layers at the level of the inner nuclearlayer.12 Paracentral acute middle maculopathy has been re-ported in association with various retinal disorders,including CRVO and diabetic retinopathy,1,10–12 and maybe attributable to ischemia of the intermediate and deepretinal capillary plexuses, anatomically located at theinner and outer zones of the INL, respectively. This studyhas shown that paracentral acute middle maculopathymay be variably identified in eyes with retinal arterialocclusive disease and its occurrence depended on thelocation and extent of the retinal arterial circulationcompromise. Retinal arterial occlusive disease frequentlycaused lesions with both superficial and deep capillaryischemia, while other cases showed only deep capillaryischemia. With SD OCT, the ischemic lesions appearedthickened and hyperreflective in the acute phase andinvariably evolved into thinning and atrophy of therespective retinal layers in the chronic phase (Figure 7).

A prominent middle limiting membrane (p-MLM) sign,detected on SD OCT imaging, is a recently introducedterm that refers to an inner retinal hyperreflective line at

the level of the outer plexiform layer.16 This is synonymouswith paracentral acute middle maculopathy but fails to takeinto account the paracentral and placoid opacification thatoccurs at the inner nuclear and inner plexiform layers.Moreover, the p-MLM sign is variably present and fails toaccount for the etiologic mechanism of deep capillaryischemia.1,10–12 Hence, the terms paracentral acutemiddle maculopathy and deep capillary ischemia havebeen adopted throughout this study.This study presented several cases of CRAO and BRAO

with clinical and angiographic evidence of arterial occlu-sion and associated superficial and deep capillary ischemiawith SD OCT analysis. Cases of retinal arterial occlusionwere also presented with isolated paracentral acute middlemaculopathy and deep capillary ischemia. Some of thesecases showed only subtle evidence of retinal artery occlu-sion, such as a faint cherry-red spot, while others werenormal clinically and angiographically. Case 6, forexample, did not show any clinical or angiographic evi-dence of CRAO, but SDOCT showed a diffuse paracentralacute middle maculopathy lesion and subsequent magnetic

FIGURE 2. Case 2: Multimodal imaging of a 91-year-old man (Patient 13) with a history of nonexudative age-related macular degen-eration (AMD) and new-onset branch retinal artery occlusion (BRAO) in the left eye (OS), showing both superficial and deep capil-lary 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) Colorfundus photograph taken at presentation showing mild retinal whitening along the inferotemporal branch retinal artery consistentwith a BRAO. (Second row, right) SD OCT imaging through the yellow line in the image on the left, showing an area of thickeningand hyperreflectivity of the inner retinal layers at the area closer to the optic nerve (yellow arrow). There is a separate area locatedtemporally 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 imagingthrough the yellow line in the image on the left, showing an area of superficial capillary ischemia (yellow arrow) and an area of su-perficial and deep capillary ischemia (white arrow).


resonance angiography identified carotid dissection. Thesecases of diffuse isolated paracentral acute middle maculop-athy indicating widespread deep capillary ischemia arelikely the result of a CRAO. The lack of angiographiccompromise at the time of presentation may be the resultof subsequent recanalization and reperfusion or vasospasmof the central retinal artery. However, one may arguethat the diagnosis of CRAO may be unsubstantiated andthat these cases should just be referred to as paracentral

acute middle maculopathy. Despite having only middleretinal layer involvement, patients with isolated diffuseparacentral acute middle maculopathy may suffer profoundvisual loss, consistent with CRAO.The presence of different levels of ischemia within the

spectrum of retinal artery occlusion may be attributable toa variation in ischemic susceptibility. We propose thatthe deep capillary plexus may be more vulnerable to anischemic insult, as it may reside in a watershed region of

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 inferotem-poral to the central fovea, consistent with a BRAO. (Top row, right) Fluorescein angiography (FA) was normal and showed no ev-idence 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 opticalcoherence tomography showing thickening and hyperreflectivity of the middle layers and paracentral middle maculopathy (arrows).


oxygen supply. Studies on intraretinal oxygen tension in catand rat retinas have shown that there is a dip in the oxygentension levels in themiddle retinal layers (at the level of theINL) compared to the inner and outer retinal layers.17–19

Extrapolation to human eyes supports the presence of awatershed zone in the middle retinal layers, therebyexplaining the presence of isolated paracentral acute

middle maculopathy in the absence of superficial capillaryischemia in the setting of retinal vasculopathy includingretinal artery and vein occlusions.11 In addition, in eyeswith contiguous superficial and deep capillary ischemia,paracentral acute middle maculopathy was found predomi-nantly at the edges rather than at the core of ischemic le-sions. Since there may be a greater ischemic insult at the

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 whit-ening along the cilioretinal artery. (Right, top row)Near-infrared reflectance (NIR) and corresponding spectral-domain optical coher-ence 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 onNIR corresponding to paracentral acute middle maculopathy lesion on SDOCT, representing deep capillary ischemia. (Right, bottomrow)NIR and corresponding SDOCT through the center of retinal whitening inferior to the fovea showing the hyporeflective area onNIR corresponding to thickening and hyperreflectively of the inner andmiddle retinal layers on SDOCT, representing superficial anddeep capillary ischemia.

FIGURE 5. Case 5: Multimodal imaging of an 81-year-old woman (Patient 2) with central retinal artery occlusion (CRAO) in theleft eye (OS) showing both superficial and deep capillary ischemia in the acute phase. (Top row, left) Color fundus photographshowing the characteristic ‘‘cherry-red spot’’ appearance in acute CRAO. (Top row, right) Spectral-domain optical coherence tomog-raphy (SD OCT) through the fovea showing thickening and hyperreflectivity of the inner and middle retinal layers, indicating bothsuperficial 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 foveaand relative blocking of incoming light by the paracentral ischemic lesions. (Bottom row) Sequential fluorescein angiography showingdelayed filling in the retinal arterial circulation.


core in the central distribution of the occluded artery thanat the edges, owing to adjacent perfused vascular retina, thisfurther supports our theory that the deep capillary plexus re-sideswithin themore vulnerable watershed zone andmay bemore susceptible to ischemia. Another plausible explana-tion for the appearance of paracentral acute middle macul-opathy at the perifoveal region may be the physiologicalpaucity of superficial capillaries in this area.20

In this study of retinal arterial occlusive disease, weidentified cases with isolated paracentral acute middle

maculopathy but failed to note any cases with isolated su-perficial capillary ischemia. Isolated ‘‘cotton-wool spots’’may represent a different mechanism or level of occlusion(ie, pre–capillary arteriolar occlusion or superficial capil-lary ischemia, as occurs with diabetic retinopathy).1 Ourinability to identify isolated superficial capillary ischemiain association with retinal artery occlusion may be attribut-able to selection bias and/or to the limitations of a retro-spective study. Other limitations of this study include thesmall sample size and nonconsecutive series in which the

FIGURE 6. Case 6: Multimodal imaging and carotid angiography of a 55-year-old woman (Patient 14) with carotid artery dissectionand central retinal artery occlusion (CRAO) in the left eye (OS) showing isolated paracentral acute middle maculopathy in the acutephase. (Top row, left) Color fundus photograph was normal. (Top row, second from left) Fundus autofluorescence was normal. (Toprow, third from left) Fluorescein angiography (FA) was normal. (Top row, right) FA in the late phase showing no evidence of perfu-sion insufficiency. (Second row) Near-infrared reflectance (NIR) and corresponding spectral-domain optical coherence tomography(SDOCT) through the fovea showing an area of hyporeflectance onNIR surrounding the fovea, corresponding to isolated paracentralacute middle maculopathy lesion on SDOCT. (Third row) Magnified view of the SD OCT showing isolated paracentral acute middlemaculopathy surrounding the fovea, indicating isolated deep capillary ischemia. There is a hyperreflective quality at the central fovearelated to the contrast effect brought about by transmission of incoming light at the fovea and relative blocking of incoming light by theparacentral acute middle maculopathy lesions. (Bottom row, left) Humphrey visual field test showing a normal visual field OD and acentral scotoma OS corresponding to the central ischemic lesion. (Bottom row, right) Carotid angiography showing a carotid dissec-tion on the left side.


prevalence of paracentral acute middle maculopathycannot be accurately analyzed. Future prospective andlarger consecutive case studies may be able to show thatparacentral acute middle maculopathy occurs more or lessfrequently than noted in this study. More advanced tech-nologies such as en face systems and OCT angiographymay be able to better analyze and characterize abnormal-ities of the deep capillary plexus.

In the cases of CRAO with paracentral acute middlemaculopathy, with or without involvement of the innerretinal layers, we identified a characteristic hyperreflectivequality of the central fovea. This interesting finding maybe attributable to a contrast effect in which swelling andhyperreflectivity in the paracentral regions cause relativeblocking of incoming light, while the incoming light at thecentral fovea is fully transmitted. This appearance may be

the SD OCT correlate of a cherry-red spot and may alertthe clinician to search for evidence of superficial and deepcapillary ischemia with SD OCT analysis (Figures 5 and 6).In conclusion, SD OCT imaging revealed the full spec-

trum of ischemic changes in retinal arterial occlusive dis-ease, including superficial capillary ischemia when theinner retinal layers are involved and deep capillaryischemia or paracentral acute middle maculopathy whenthe middle retinal layers are involved. A combination ofboth was found to be most common in this study. SDOCT imaging may be capable of detecting paracentralacute middle maculopathy in cases where the FA is normalwithout any evidence of nonperfusion or ischemia and maybe a more sensitive tool for evaluating retinal arterialocclusive disease and, more specifically, characterizingthe nature and extent of macular ischemia.

THEAUTHORSHAVE COMPLETEDAND SUBMITTED THE ICMJE FORM FORDISCLOSUREOF POTENTIAL CONFLICTSOF INTEREST.Financial Disclosures: K. Bailey Freund: Consultant to Heidelberg Engineering, Regeneron, Genentech and Bayer HealthCare, and Thrombogenics. DavidSarraf: 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 pub-lication 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.); datamanagement (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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FIGURE7. Summary of the spectrum of retinal capillary ischemic lesions seenwith spectral-domain optical coherence tomography inretinal arterial occlusive disease in the acute and chronic phase.


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Biosketch

Suqin Yu, MD is a medical retina specialist. She received her medical degree from Shanghai Medical University and masterdegree from Shanghai Medical College of Fudan University. Dr Yu is currently an Associate Professor of the Department ofOphthalmology, Shanghai Jiaotong University affiliated Shanghai First People’s Hospital, China.

63.e1 JANUARY 2015AMERICAN JOURNAL OF OPHTHALMOLOGY

Biosketch

Dr Claudine E. Pang graduated with Distinction from the National University of Singapore, completed ophthalmologytraining with the Royal College of Surgeons in Edinburgh (FRSCEd) and College of Ophthalmologists, Academy ofMedicine in Singapore (FAMS). She has received 2 vitreoretinal fellowships at the Vitreous Retina MaculaConsultants of New York, Manhattan Eye, Ear and Throat Hospital, followed by the William H. Ross VitreoretinalSurgical Fellowship at the University of British Columbia, Vancouver. Her interests are in macular diseases,vitreomacular surgery and retinal imaging.

VOL. 159, NO. 1 63.e2THE SPECTRUM OF RETINAL ISCHEMIA IN RETINAL ARTERY OCCLUSION

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