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 Peoples 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: dsarraf@ucla.edu
0002-9394/$36.00
http://dx.doi.org/10.1016/j.ajo.2014.09.027

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;159:5363.
! 2015 by Elsevier Inc. All rights reserved.)

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.16 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.1012 Paracentral acute middle
maculopathy has been described in association with acute
macular neuroretinopathy,12,13 diabetic retinopathy,1 retinal

ELSEVIER INC. ALL

RIGHTS RESERVED.

53

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 1791 years), were included in the study.
The mean duration of follow-up was 20 6 26.2 months
(range 0120 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 4), BRAO (n 4), and cilioretinal artery occlusion (n 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

70

OS
OD
OS
OD
OD

CF
20/80
CF
20/25
20/150

CF
20/60
CF
20/25
20/40

19

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

39

30

26

OD
OS
OS
OD
OD
OS
OD
OS
OD
OS
OD
OS
OD

31

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

SCIDCI
SCIDCI
SCIDCI 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

SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI AMD
Only DCI

3
4
49
49
50

BRAO
BRAO
CRVOCRAO
BRAO
BRAO

SCIDCI
SCIDCI
SCIDCI
Only DCI
SCIDCI

BRAO

SCIDCI

0
9
2
25
27
8
1
11
62
62
11
11
5

BRAO
CRVOCRAO
CRVOCRAO
CRVOCRAO
CRVOCRAO
CRVOBRAO
CRVOBRAO
CRVOCRAO
BRAO
BRAO
BRAO
BRAO
BRAO

Only DCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
SCIDCI
Only DCI

4
6
0
80
1
0

BRAO
BRAO
Cilioretinal AO
Cilioretinal AO
CRAO
CRAO

Only DCI
SCIDCI RD, s/p PPV
Only DCI
Only DCI Macular hole
Only DCI
Only DCI

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 age-related macular degeneration; AO artery occlusion; BCVA best-corrected visual acuity; BRAO branch retinal artery occlusion;
CF counting fingers; CRAO central retinal artery occlusion; CRVO central retinal vein occlusion; CSC central serous chorioretinopathy; DCI
deep capillary ischemia; DM diabetes mellitus; DVT deep vein thrombosis; HTN hypertension; LP light perception; MI myocardial infarction;
N/A not applicable; NPDR nonproliferating diabetic retinopathy; POAG primary open-angle glaucoma; PPV pars plana vitrectomy; RHD
rheumatic heart disease; SCI superficial capillary ischemia; SLE systemic lupus erythematosus; s/p status post; VSD ventricular septal defect.

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THE SPECTRUM OF RETINAL ISCHEMIA IN RETINAL ARTERY OCCLUSION

55

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 .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 .45).
Here, we describe some representative cases to showcase
the spectrum of SD OCT findings in retinal arterial occlusive disease.
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 1:

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

! CASE 2:

56

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).
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 3:

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 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 alonein particular during the chronic
phasemay 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

THE SPECTRUM OF RETINAL ISCHEMIA IN RETINAL ARTERY OCCLUSION

57

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,1,1012 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.1,1012 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
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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.1719
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
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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, precapillary 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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61

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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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 Peoples 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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