SURVEY OF OPHTHALMOLOGY VOLUME 55 ! NUMBER 1 !

JANUARY–FEBRUARY 2010

MAJOR REVIEW

Ocular Ischemic Syndrome

Efstratios Mendrinos, MD,1 Theofilos G. Machinis, MD,2
and Constantin J. Pournaras, MD1

1
Vitreo-retinal Unit, Department of Ophthalmology, Geneva University Hospitals, Geneva, Switzerland;
and 2Harold F. Young Neurosurgical Center, Virginia Commonwealth University, Richmond, Virginia, USA

Abstract. Ocular ischemic syndrome encompasses a spectrum of clinical findings that result from
chronic ocular hypoperfusion. It is relatively uncommon, and the diagnosis may be difficult to make
because of its variable presentations. The presence of an ocular ischemic syndrome always implies
underlying severe carotid occlusive disease and may be its sole clinical manifestation. It may also result
from other causes of reduced blood flow to the eye and the orbit such as systemic vasculitis. Besides
visual loss and ocular/orbital pain, affected patients are also at risk for developing cerebral and
myocardial infarction. Establishing the diagnosis is therefore essential with respect not only to visual
prognosis but also to patient survival. Ophthalmologists have an important role in early diagnosis and
in coordinating the systemic evaluation of patients. Referral to the neuroradiologist and the
neurovascular specialist is warranted. We present the current knowledge on the ocular ischemic
syndrome. (Surv Ophthalmol 55:2--34, 2010. ! 2010 Elsevier Inc. All rights reserved.)

Key words. carotid artery imaging ! carotid artery occlusion ! carotid reconstructive
surgery ! chronic ocular hypoperfusion ! collateral circulation ! light-induced transient
visual loss ! ocular angina ! ocular ischemic syndrome ! ocular neovascularization !
reversed ophthalmic artery blood flow

I. Introduction progressive hypoperfusion of the eye may lead to

Carotid artery disease represents a major cause of
morbidity and mortality. Both stenosis and occlusion
of the common (CCA) or internal (ICA) carotid
arteries are responsible for ipsilateral ocular signs
and symptoms that may herald a devastating cere-
bral infarction.20 Moreover, ocular signs and symp-
toms may be the first manifestations of carotid artery
disease.65 The most common ocular symptom,
which occurs in 30--40% of patients with carotid
atherosclerotic occlusive disease is ipsilateral tran-
sient visual loss.31,87,99 Transient monocular visual
loss is the hallmark of carotid insufficiency.110
Although the majority of ophthalmic complications
related to carotid artery disease are the result of
occlusion of retinal vessels by emboli, chronic and
global ocular ischemia.21
II. Historical Review
In 1963, Hedges described retinal vessel changes
(dilation of the retinal veins with or without a sausage-
like appearance) and peripheral blot hemorrhages in
a 48-year-old white man with complete obstruction of
the left ICA.99 He attributed these findings to retinal
hypoxia induced by carotid artery insufficiency.
Kearns and Hollenhorst also reported the presence
of venous dilation in association with mid-peripheral,
dot, and blot hemorrhages, superficial flame-shaped
nerve fiber layer hemorrhages, and microaneurysms
in patients with carotid artery obstruction and coined

2
! 2010 by Elsevier Inc. 0039-6257/09/$--see front matter
All rights reserved. doi:10.1016/j.survophthal.2009.02.024
OCULAR ISCHEMIC SYNDROME
the description venous stasis retinopathy to emphasize
changes that occur in the retinal venous circula-
tion.135 They found this retinopathy in 5% of their
patients with unilateral stenosis or occlusion of the
ICA, all of whom had a low central retinal artery (CRA)
pressure on the affected side,135 suggesting that
retinal venous changes are caused by decreased
arterial perfusion pressure and retinal blood flow
and subsequent retinal hypoxia. In 1965, Knox
reported five patients presenting with anterior seg-
ment inflammation as a result of occlusive branchio-
cephalic vascular disease. He felt this was an ocular
inflammatory response to a generalized ischemic state
and called this condition ischemic ocular inflamma-
tion.143 Young255 and Diener63 used the terms of
ischemic oculopathy and ischemic ophthalmopathy, respec-
tively, to describe ischemic changes related to carotid
artery occlusive disease not limited to the posterior
segment of the eye, but also present in the anterior
segment of the eye. Overall, the presence of both
posterior and anterior segment signs and symptoms is
referred to as ocular ischemic syndrome (OIS).
III. Epidemiology and Pathogenesis
Ocular ischemic syndrome occurs at a mean age
of 65 years and is rare before 50. Men are affected
twice as often as women,29,133 reflecting the higher
incidence of atherosclerotic disease in males. No
racial predilection exists. Bilateral involvement may
occur in up to 22% of cases.8,24,27,29,59,115,176,222 The
incidence of OIS is not precisely known, but is
estimated at 7.5 cases per million persons every year
by Sturrock and Mueller.227 This is probably an
underestimation as OIS may be misdiagnosed as
other ocular vascular diseases such as retinal vein
occlusions and diabetic retinopathy or may be
masked by them.
Kearns and Hollenhorst diagnosed OIS in 4% of
their patients with carotid occlusive disease,135 and
Kearns et al reported that of patients with occlusion
of the ICA undergoing surgical anastomosis
between the superficial temporal artery and the
middle cerebral artery, 18% presented with OIS.133
Up to 29% of patients with a symptomatic carotid
occlusion manifest retinal vascular changes that are
usually asymptomatic, and 1.5% of them per year
progress to symptomatic OIS.142
Ocular ischemic syndrome develops especially in
patients with poor collateral circulation between the
internal and external carotid arterial systems or
between the two ICAs. Those with well-developed
collateral circulation may not develop OIS even with
total occlusion of the ICA. On the contrary, in those
with poor collaterals a stenosis of less than 50% of the
3
ICA may be sufficient for the OIS to develop.176
Insufficient collateral vascular pathways in OIS patients
also explain the occurrence of cerebral infarctions and
the poor neurologic prognosis associated.53 Indeed,
patterns of occlusion vary from less than 50% stenosis
to complete occlusion of at least one CCA or one ICA,
often accompanied by occlusion or stenosis of the
opposite carotid arterial system.18,37,76,169,206,218
Patients who develop OIS show decreased blood
flow in the retrobulbar vessels and reversal of blood
flow in the ophthalmic artery (OA).53,54,94,113,138,139
In these cases, OA behaves as a steal artery shunting
blood flow away from the eye to the low-resistance
intracranial circuit causing further reduction of
retrobulbar blood flow and leading to hypoperfusion
and subsequently ischemia of ocular tissues.24,54,82
Overall, the degree of stenosis, the presence or
absence of collateral vessels, variations in the anasto-
motic channels that compensate for the occluded
vessels as well as the chronicity of the carotid artery
disease, its bilaterality, and associated systemic vascular
diseases that further impair the ocular blood supply
are implicated in the pathogenesis of the OIS.53,176
IV. Clinical Presentation
Table 1 summarizes the ophthalmic clinical signs
that can be observed in eyes with OIS.
A. SYMPTOMS
1. Visual Loss
Brown et al performed a retrospective study of 43
patients with OIS and found a decrease in visual
acuity (VA) in 91% of the affected eyes.29 In 67% of
the eyes, the visual loss occured gradually over
a period of weeks to months. In 12% of the eyes, it
occured over a period of days, whereas in another
12% the loss was sudden and was noted over
a period of seconds to minutes or upon awakening.
In the Mizener et al prospective study of 39 eyes,
visual loss at the first presentation occurred sud-
denly in 41% of the eyes, was gradual in 28%, and
21% had no visual loss.176
At initial presentation, in the series reported by
Brown et al, 35% of eyes had a VA of 20/20 to 20/40
and in 35% had vision of counting fingers or
worse.29 Similarly, in 52 patients studied by Sivalin-
gam et al, 43% of the affected eyes had an initial VA
of 20/20 to 20/50, and 37% had vision of counting
fingers or worse.222 Mizener et al reported initial VA
of 20/40 or better in 15% of their cases, whereas
65% had VA of 20/400 or less.176
Visual fields on presentation also vary greatly from
normal (23%), to central scotoma (27%), to nasal
defects (23%), to centrocaecal defects (5%), to the
4 Surv Ophthalmol 55 (1) January--February 2010
TABLE 1
Clinical Presentation of the Ocular Ischemic Syndrome
Anterior Segment
! Conjunctival and episcleral injection
! Corneal edema (Descemet’s folds, bullous
keratopathy)
! Corneo-scleral melting
! Spontaneous hyphema
! Iris atrophy
! Fixed semi-dilated pupil or sluggish reaction to light
with relative afferent pupillary defect
! Anterior and posterior synechia
! Uveal ectropion
! Rubeosis iridis
! Neovascular glaucoma
! Iridocyclitis (flare, cells, keratic precipitates)
! Asymmetric cataract
Posterior Segment
! Narrowed retinal arteries
! Dilated retinal veins
! Retinal hemorrhages
! Microaneurysms
! Macular capillary telangiectasias
! Retinal arteriovenous communications
! Cotton-wool spots
! Cherry-red spot
! New vessels on the disk
! New vessels elsewhere
! Choroidal neovascular membrane
! Vitreous hemorrhage
! Cholesterol emboli
! Spontaneous retinal arterial pulsations
! Anterior ischemic optic neuropathy
! Cobblestone degeneration and wedge-shaped areas of
chorio-retinal atrophy
Orbital infarction syndrome
! Orbital pain
! Anterior and posterior segment ischemia with
intraocular inflammation and hypotony
! Ophthalmoplegia
! Ptosis
! Corneal hypoesthesia
presence only of a central or temporal island
(5%).176
A history of transient visual loss is present in
approximately 10--15% of patients with OIS.29,176
This is most frequently caused by transient emboliza-
tion of the CRA or its branches, but vasospasm may
also play a role.250 In these cases, a dark or black shade
spreads across the visual field that lasts for a few
seconds to minutes. Less commonly, severe carotid
artery disease causes transient visual loss as a result of
choroidal hypoperfusion. Conditions that either
increase retinal metabolic demands or decrease
perfusion pressure can precipitate transient visual
loss and reflect the inability of a borderline ocular
circulation to maintain stable the ocular blood flow.
This has been reported following exposure to bright
light,64,81,125,204,248 postural change,108 and after
eating a meal.152,183,194 Visual loss resulting from
MENDRINOS ET AL
hypoperfusion of the the choroid often lasts several
minutes to hours and may be associated with positive
visual phenomena.118,235
2. Pain
Pain may be present in up to 40% of the eyes with
OIS. Even though 94% of those with pain have iris
neovascularization, only 70% of them have an
intraocular pressure (IOP) greater than 25 mm
Hg.29 Pain may be the result of increased IOP or
may be ischemic in origin. Ischemic pain begins
gradually over hours to days and is described as
a dull, constant ache in the affected eye, over the
orbit, upper face, and temple, and may worsen when
the patient is upright. Lying down relieves or lessens
pain. The description ocular angina may be used to
describe this discomfort.
Kearns et al reported ischemic pain in 3 out of 60
(5%) patients with ipsilateral carotid occlusion,
most of them chronic,133 and Mizener et al reported
ocular/orbital pain in 13% of affected eyes.176
Ischemic pain may be confused with that from
secondary glaucoma, but pain in eyes with OIS
would not be explained by a slight IOP elevation.
Pain from both increased IOP and ischemia may be
present in the same patient. In older patients, giant
cell arteritis should be excluded.
B. OCULAR MANIFESTATIONS
1. Anterior Segment Signs
Anterior segment ischemia may be the sole mani-
festation of carotid artery disease.158 Examination of
the anterior segment may reveal dilated conjunctival
and episcleral vessels.21,41,62,65,137,174,175,227 Episcleral
injection may be a sign of collateral blood flow from
the external carotid artery (ECA) in the presence of an
ICA occlusion.56 Corneal edema with folds of
Descemet’s membrane from chronic ischemia may
lead to bullous keratopathy.62,137,227 Scleral melting
has been described in a patient with OIS secondary to
subtotal occlusion of the ipsilateral ICA.214
Iris atrophy123,144 and neovasularization are also
signs of chronic anterior segment ischemia.27,29,
41,57,62,107,113,118,126,137,163,175,176,206,225
The pupil
may be fixed and semi-dilated as a result of ischemia
of the pupil’s sphincter or may show a sluggish
reaction to light and a relative afferent pupillary
defect, reflecting significant retinal ische-
mia.89,137,140,163,177 Neovascularization may be most
prominent at the pupillary border or predominates
at the irido-corneal angle leading to peripheral
anterior synechiae and angle closure.118,126,137,176 In
eyes with severe iris neovascularization, hyphema
and uveal ectropion may be observed.123,227 The
OIS should be suspected when iris neovasculariz
OCULAR ISCHEMIC SYNDROME
ation is seen in non-diabetic eyes or in eyes without
a history of central retinal venous occlusion.
Iris neovascularization leads to increased IOP and
neovascular glaucoma.41,52,57,103,111,118,137,160,197,224,
225,242
Some patients may have an IOP in the normal
range despite fibrovascular tissue closing the angle,
even ocular hypotony, because of ischemia of the
ciliary body and reduced aqueous humor produc-
tion.27,29,52,80,89,177,178 This is probably the mecha-
nism of the IOP elevation sometimes observed
following surgical re-establishment of ocular blood
flow.52,89,133,172,175,177,242,255 In a series of 43 patients
with the OIS, two-thirds of whom had iris neo-
vascularization, only one-third had IOP measure-
ments over 22 mm Hg.29
A mild iritis may be noted in about 20% of
patients with OIS.21,29,57,118,137,143,177,225 The flare is
usually more pronounced than the cellular reaction
and is often associated with iris neovasculariza-
tion.27,29,137,163,176 Keratic precipitates are un-
usual.21,29 Lens opacities, even formation of
a mature cataract, may occur in the end stages of
OIS.21,29,41,65,144,174,176,197,225,227
2. Posterior Segment Signs
Posterior segment signs of carotid occlusion are
more frequent than anterior segment signs.175 The
retinal arteries are generally narrowed, and the
retinal veins are often irregularly dilated but not
tortuous.27,29,41,62,126,137,163,169,177,225 The venous di-
latation may be accompanied by beading that is not
as extensive as that seen in eyes with severe non-
proliferative or proliferative diabetic retinopathy. In
eyes with central retinal vein occlusion (CRVO),
retinal veins are both dilated and tortuous. The
differences in the appearence of retinal veins in eyes
with OIS and CRVO may be because in OIS there is
compromized inflow, whereas in CRVO there is
outflow obstruction.88 Nevertheless, in some eyes
with OIS both retinal arteries and veins are
narrowed.
Retinal hemorrhages are seen in about 80% of the
affected eyes. Hemorrhages are mostly located in
the mid-peripheral retina, but may also be in the
posterior pole (Fig. 1).41,163,169 Hemorrhages are
rarely numerous, almost never confluent, and
mostly located deep in the retinal layers, only
occasionally at the level of the nerve fiber layer;
thus, dot and blot are most common than flame-
shaped hemorrhages.29 Rarely, they may be white-
centered.105 Hemorrhages probably result from
leakage from the small retinal vessels that have
sustained ischemic endothelial damage or from
rupture of capillary microaneurysms.
5
Fig. 1. Posterior segment findings in a patient presenting
with the ocular ischemic syndrome. The retinal veins are
dilated but not tortuous associated with peripapillary
flame-shaped and posterior pole blot hemorrhages.
Microaneurysms are frequently observed in OIS,
especially on fluorescein angiography. They may be
macular, as in eyes with diabetic maculopathy, but
are most often located outside the major vascular
arcades in the mid-periphery.27,29 Diffuse macular
capillary telangiectasia has been reported as a pri-
mary retinal finding in association with bilateral
common carotid artery occlusion.32 Macular capil-
lary telangiectasia together with microaneurysms
may result in perifoveal leakage and macular edema
with decreased VA.26,32 Brown reported macular
edema demonstrated by fluorescein angiography in
seven of 51 eyes (14%) with OIS caused by ipsilateral
carotid stenosis of 90% or more.26 Retinal arterio-
venous communications proximal to extensive areas
of avascular retina may also occur in OIS.23,227
A cherry-red spot is seen in about 12% of eyes,
either as a result of embolic occlusion of the CRA or,
more often, when IOP increases and exceeds the
perfusion pressure within the CRA in eyes with
neovascular glaucoma.29 Further posterior segment
findings include cotton-wool spots (6%), retinal
emboli, and retinal arterial pulsations, either spon-
taneous or induced by light digital palpation of the
globe.29,41,62,118,137,177 In the peripheral retina there
may be wedge-shaped areas of chorio-retinal atrophy
attributed to choroidal ischemia.75,123
Anterior ischemic optic neuropathy may occur in 2--
18% of affected eyes.25,29,62,246 In eyes with neovascular
glaucoma, optic disk cupping occurs.52,137,197 In some
cases, chronic reduction of the retrobulbar blood flow
may lead to normal-tension glaucoma.94
6 Surv Ophthalmol 55 (1) January--February 2010 MENDRINOS ET AL

New vessels formation may occur at the optic disk
or in the retina.27,28,41,118,137,206,225 New vessels on the
disk appear more common than new vessels
elsewhere (35--37% vs 8--10% in the series of Brown
et al).27,29 New vessels can bleed with resulting
vitreous hemorrhage and, rarely, severe fibrovascular
proliferation.27 A single case of subfoveal choroidal
neovascular membrane has been described in
a 54-year-old patient with OIS.75
which may develop in the absence of neovasculariza-
tion at the iris border/surface. As discussed pre-
viously, IOP may be normal range even if the angle is
closed. Dilated fundus examination should always be
performed, with attention to the presence of irregu-
larly dilated retinal veins, narrowed arteries, and
spontaneous retinal arterial pulsations. The mid- and
peripheral retina should be examined for the
presence of new vessels, dot and blot retinal
hemmorhages, and emboli.

3. Orbital Infarction Syndrome

Rarely, ischemia of all intraorbital and intraocular
structures may occur in OIS causing the orbital
infarction syndrome, consisting of orbital pain, anterior
and posterior segment ischemia with intraocular
inflammation and hypotony, ophthalmoplegia, ptosis,
and corneal hypoesthesia. Involvement of the entire
orbit develops in the absence of adequate collateral
supply from the ECA, contralateral carotid system,
and other cervical arteries. Two cases of orbital
infarction syndrome in association with ipsilateral
ICA or CCA occlusion have been reported in the
literature and led to irreversible blindness.22,240
When examining a patient suspected to have OIS,
special attention should be given during slit-lamp
anterior segment examination to the presence of
conjuctival/episcleral vessel dilation, corneal edema,
flare in the anterior chamber, and iris neovasculari-
zation. Gonioscopy should be performed before
pupil dilation to assess angle neovascularisation,
V. Differential Diagnosis
Diabetic retinopathy and CRVO are the two most
likely conditions to be confused with OIS. 41,134
Table 2 lists the principal clinical and angiographic
signs that help to differentiate these three diagno-
ses. An important differentiating feature among
OIS, CRVO, and diabetic retinopathy is low retinal
artery pressure; light digital pressure on the lid
induces retinal arterial pulsations in eyes with OIS.
Diabetic retinopathy may coexist with OIS19,116,247
and we recommend that diabetic patients who have
unilateral retinopathy or marked assymetry of
retinopathy67,237 be examined for possible carotid
occlusive disease. About 20% of such patients have
hemodynamically significant carotid artery stenosis,
but this stenosis may be contralateral or ipsilateral to
the eye with the more severe diabetic retinopathy.67
The differential diagnosis of OIS should include
the hyperviscosity syndromes.121,192,216 Fundus

TABLE 2
Differential Diagnosis of Ocular Ischemic Syndrome (OIS), Central Retinal Vein Occlusion (CRVO), and Diabetic
Retinopathy (DR)
Features OIS CRVO DR
Posterior segment signs
Retinal veins Dilated but not tortuous Dilated and tortuous Dilated and beaded
Hemorrhages (location) Dot and blot Flamme-shaped (all Dot and blot (posterior
(mid-periphery) quadrants) pole and mid-periphery)
Microaneurysms Common (mid-periphery) Uncommon Common (posterior pole)
(location)
Other microvascular Macular telangiectasis, Opto-ciliary shunts, Intraretinal microvascular
abnormalities retinal arteriovenous capillary drop-out abnormalities, capillary
communications, drop-out
capillary drop-out
Hard exudates No Rare Common
Optic disk Normal Swollen (commonly) Diabetic
papillopathy(rarely)
Central retinal artery Decreased Normal Normal
perfusion pressure
Fluorescein angiography
Arterio-venous transit Prolonged Prolonged Usually normal
time
Retinal vessel staining Arteries O Veins Veins O Arteries Usually absent
Macular edema Rare Common Common
Choroidal filling Delayed, patchy Normal Usually normal
OCULAR ISCHEMIC SYNDROME
manifestations caused by serum or blood hypervis-
cosity include optic disk swelling, retinal capillary
microaneurysms, cotton-wool spots, retinal hemor-
rhages, dilated retinal veins, and retinal venous
occlusion.33,192 Complete blood cell count with
differential, serum protein electrophoresis, and
immunoelectrophoresis should be obtained. Ocular
ischemic syndrome should also be considered in the
differential diagnosis of all new-onset uveitis in
patients over the age of 50.41,143,175
VI. Systemic Associations
Atherosclerosis of the carotid vascular system is
the major cause of OIS29 and may be its initial
manifestation.17,76,126 Atherosclerotic plaques are
usually located at the site of carotid bifurcation or
at the proximal segment of the ICA, but rarely an
intracranial carotid artery stenosis may lead to
OIS.164 In general, a degree of stenosis of 90% or
more of the ipsilateral carotid arterial system is
present in eyes with OIS.27 Occassionally, the site of
occlusion is the OA31,161 or bilateral ECAs.4
Patients with OIS often have systemic vascular
diseases that are related to atherosclerosis. In 52
patients studied prospectively by Sivalingman et al,
history of ischemic heart disease, previous cerebro-
vascular accident, and peripheral vascular disease
was present in 48%, 27% and 19% of the patients,
respectively. Seventy-three percent (73%) had sys-
temic arterial hypertension, and 56% were di-
abetic.223 The prevalence of both systemic arterial
hypertension and diabetes were significantly higher
among patients with OIS than in an age- and sex-
matched control population (26% and 6.4%, re-
spectively). The neurologic prognosis (including
both patients who underwent carotid artery surgery
and those who did not) was also worse among
patients with OIS. The average stroke rate was 4%
per year in patients with OIS compared to 0.49% per
year in the control group.
Similarly, Mizener et al studied 32 patients with
OIS and found that the incidence of diabetes,
coronary artery disease, and cerebrovascular disease
was much higher in patients with OIS than in
a comparable general population.176 Associated
systemic diseases included diabetes mellitus (56%),
systemic arterial hypertension (50%), coronary
artery disease (38%), and previous cerebral in-
farction or transient ischemic attack (31%). More-
over, they found that OIS was the initial
manifestation of carotid occlusive disease in 69%
of the patients. These results are in accordance with
the earlier study by Brown and Magargal who found,
in a retrospective series of 43 patients, systemic
7
arterial hypertension in 56%, diabetes mellitus in
43%, atherosclerotic cardiovascular disease in 35%,
and previous cerebrovascular accident or transient
ischemic attacks in 26% of their patients.29
Less commonly, the OIS may appear in patients
with giant cell arteritis (GCA),91 aortic arch syn-
drome (AAS), 98 and Takayasu arteritis.46 Individual
cases of OIS associated with carotid artery dissec-
tion,66 hyperhomocysteinemia,115 radiotherapy of
the neck with carotid occlusion,156 dysthyroid
orbitopathy,219 moya-moya disease and neurofibro-
matosis,15 and scleroderma146 have been reported.
VII. Giant Cell Arteritis
GCA is a chronic, systemic vasculitis affecting
arteries with a continuous layer of elastic tissue,
called the internal elastic lamina, that forms the
boundaries between the intima and the media of the
vessel wall. Medium- and large-sized arteries arising
from the aortic arch are primarily, but not exclu-
sively, involved. The superficial temporal, ophthal-
mic, posterior ciliary and vertebral arteries are most
commonly affected.35 The most common ocular
complications are ischemic optic neuropathy (usu-
ally anterior but occasionally posterior), transient
visual loss, CRA occlusion (CRAO), cilioretinal
artery occlusion, diplopia, and oculomotor
palsies.35,97 Ocular ischemic syndrome is encoun-
tered as a rare manifestation of GCA. Such patients
present with anterior ischemic optic neuropathy
associated with corneal edema, Descemet’s folds,
uveitis, accentuated lens opacities and ocular
hypotony.38,91,114,239
The cases reported of OIS caused by GCA result
from acute inflammatory thrombosis of multiple
ciliary arteries, leading to ischemia of the anterior
and posterior segment (almost invariably anterior
ischemic optic neuropathy). Although signs of
ocular ischemia, these findings do not result from
chronic and progressive hypoperfusion of the eye as
seen in typical OIS, but rather are acute manifesta-
tions in the territoty of ciliary arteries and may
regress rapidly following corticosteroid treatment.
VIII. Aortic Arch Syndrome
Aortic arch syndrome encompasses a variety of
entities that cause progressive obliteration of vessels
arising from the aortic arch. Patients with AAS may
present with symptoms and signs of ocular, cerebral,
and/or upper extremity hypoperfusion as a result
of the gradual reduction in blood flow to the eye,
head, and upper extremities.98,124 The ocular
manifestations of AAS are similar to those observed
8 Surv Ophthalmol 55 (1) January--February 2010
in carotid artery occlusive disease and described
herein, but are usually bilateral. Often, it is the
ocular symptoms that bring the patient to a physi-
cian’s attention, most commonly recurrent episodes
of transient visual loss.144 Other manifestations
include photopsia, visual field defects, and attacks
of pain and blurred vision that characteristically
occur when the head is raised or during exercise.
Ocular inflammatory signs and symptoms may be
the presenting manifestations of severe branchioce-
phalic vascular disease.
IX. Takayasu Arteritis
Takayasu arteritis, also known as pulseness disease
or occlusive thromboaortopathy, is an idiopathic
chronic granulomatous inflammmation affecting
the aorta and aortic arch and its main branches.
Diminished or absent pulses are present in 84--96%
of patients, associated with limb claudication and
blood pressure discrepancies between the two
arms.120 About half of the patients have ocular
symptoms; transient visual loss being the most
common.46 Takayasu retinopathy or hypotensive
retinopathy appears when the arteritis involves the
aortic arch and/or the carotid arteries with resulting
ocular ischemia. 43,46,211,238 Ocular ischemic syn-
drome may be bilateral and represent the initial
manifestation of Takayasu arteritis.147,252 The in-
cidence of Takayasu retinopathy varies from 13.5%46
to 33%. 211 In mild ocular ischemia, retinal veins
develop generalized vasodilation, and microaneur-
ysms appear. In moderate ischemia, arteriovenous
anastomoses and areas of capillary drop-out de-
velop. In severe ischemia, retinal neovascularization,
vitreous hemorrhage, neovascular glaucoma, trac-
tion retinal detachement, and optic atrophy de-
velop.9,46,193 Moreover, patients with Takayasu
retinopathy have an increased mortality rate.46
Tables 3 and 4 summarize data of case series and
case reports on OIS published in the literature.
X. Diagnosis and Ancilliary Tests
A. FLUORESCEIN ANGIOGRAPHY
Fluorescein agiography can help to establish the
diagnosis of OIS.27,29,45,62 The choroid normally
fills completely within 5 seconds after the first
appearence of the dye in the choroidal arteries.
Patchy or delayed choroidal filling can be demon-
strated in 60% of the eyes with OIS (Fig. 2).29 In
some cases the filling is delayed for more than
a minute. Prolonged choroidal filling time,
although not sensitive, is the most specific angio-
graphic sign of OIS.
MENDRINOS ET AL
A highly sensitive angiographic sign is prolonged
retinal arteriovenous time that is present in up to 95%
of eyes with OIS (Fig. 3).29 Arterial, and early and late
venous circulation times are also prolonged in eyes with
OIS,138 but retinal circulation time is not as specific as
prolonged choroidal filling time as the former can also
be observed in eyes with CRAO or CRVO.
Staining of the retinal vessels, both of the major
vessels and their branches, is another common
angiographic sign seen in 85% of the affected
eyes.27,29,177 Usually, both arteries and veins are
involved, but it is more pronounced for the arteries
(Fig. 4). Staining of the veins only can be seen in
10% of the eyes. Endothelial cell damage with
rupture of the inner blood-retina barrier due to
chronic ischemia may account for staining of the
vessel walls. When associated with diffuse leakage,
such staining may imitate the angiographic appear-
ance of frosted branch angiitis seen in inflammatory
conditions.115 The observation of a well-demarcated
leading edge of fluorescein dye is a typical angio-
graphic sign of OIS (Fig. 2).
About 15% of eyes with OIS show macular edema
at the late phase of the fluorescein angiography.26
Leakage from microaneurysms or from telangiecta-
sia and ischemic damage to the vascular endothe-
lium of small vessels account for the increased
permeability with extravasation and accumulation of
the dye resulting in increased retinal thickness.
Intraretinal fluid accumulation is usually mild to
moderate, does not have a cystoid pattern and is
often associated with hyperfluorescence of the optic
disk attributed to leakage from blood vessels. Retinal
capillary non-perfusion can be seen in some eyes,
mostly located at the mid-peripheral retina
(Fig. 5).29,177
B. INDOCYANINE GREEN ANGIOGRAPHY
Indocyanine green (ICG) angiography allows for
better evaluation of the choroidal vascular abnor-
malities in eyes with OIS.236 The arm-to-choroid
circulation time—that is, the time from the in-
jection of the dye to the first appearence of the dye
in the choroidal arteries (usually about 10 seconds),
and the intrachoroidal circulation time—that is,
the time from the first appearence of the dye in the
choroidal arteries to complete dye filling in the
choroidal veins (usually about 5--6 seconds) are both
prolonged. Choroidal hypoperfusion results in
occlusions of the choriocapillaries with areas of
vascular filling defects in the posterior pole or the
mid-periphery.
Slow filling of the watershed zones of the choroid
is another caracteristic angiographic finding in eyes
with OIS. During the arterial phase of choroidal
 TABLE 3

OCULAR ISCHEMIC SYNDROME

Case Series on the Ocular Ischemic Syndrome: Summarized Data
Ophthalmic Findings at Initial Presentation
No. of
Patients Visual Anterior Segment Posterior Carotid or Other Systemic Associations
Year Author (eyes) Symptoms Visual Acuity Signs Segment Signs Artery Disease (No. or% of patients)
1962 Smith 2 (2) VL (2/2) 20/400--HM INV, ANV, NVG Narrowed RA Ipsilateral ICA HTA (1/2)
Cherry-red spot occlusion Previous CI (2/2)
Macular edema
Pale optic disk
1963 Kearns and 7 (8) History of TVL Not reported CRAO, dilated RV Range from DM (1/7)
Hollenhorst (1/8) MA, RH, ipsilateral ICA CAD (1/7)
Pain (2/8) Spontaneous or CCA Peripheral vascular
CRA pulsations occlusion to disease (1/7)
bilateral severe Previous CI or
carotid artery TIA (5/7)
stenosis
1965 Knox 5 (6) Blurred vision 20/50--2/400 Conjuctival-ciliary Narrowed RA Atherosclerotic HTA (20%)
or VL (6/6) injection Dilated RV aortic arch DM (60%)
History of TVL Corneal edema, RH, MA syndrome (4/5) Peripheral vascular
(3/6) PAS NVD, VH Severe stenosis disease (20%)
Ocular pain (4/6) Anterior uveitis (1/5) or occlu-
+(flare, cells, sion (1/5)
KP) of ICA
INV, iris atrophy,
Mature cataract
Impaired pupil
reaction
1966 Madsen 2 (2) VL (2/2) 5/20--6.5/20 INV, NVG Narrowed RA Stenosis of the DM (1/2)
CRA pulsations ophthalmic
Dilated, sausage- artery
shaped RV, RH
1981 Diener and 9 (9) Not reported Not reported INV, NVG Dilated RV, RH, Occlusion or Previous CI or
Ruprecht Unilateral cataract MA severe stenosis TIA (4/9)
of the ipsilateral
ICA
1981 Young and 6 (6) VL (4/6) 6/9--no LP INV, NVG Narrowed RA and Range from 75% DM (at least 1/6)
Appen Pain (2/6) Sluggish or RV ipsilateral ICA Previous MI (at
unreactive Dilated RV, RH stenosis to least 1/6)
pupil to light Optic disk bilateral ICA Previous cerebral
atrophy occlusion TIA (4/6)

(continued)

9
TABLE 3 (Continued)

10
Ophthalmic Findings at Initial Presentation

Surv Ophthalmol 55 (1) January--February 2010

No. of
Patients Visual Anterior Segment Posterior Carotid or Other Systemic Associations
Year Author (eyes) Symptoms Visual Acuity Signs Segment Signs Artery Disease (No. or% of patients)

1982 Brown et al 12 (13) Gradual O 20/20--20/40 Corneal edema Narrowed RA Occlusion HTA (50%)
sudden VL to LP Aqueous flare Dilated RV, RH, or $ 80% DM (42%)
Ocular pain INV, NVG MA stenosis of Previous MI (33%)
CRAO, cherry-red ipsilateral Previous CVA or
spot ICA or CCA TIA (34%)
Spontaneous associated with
CRA pulsations 0--100% stenosis
NVE, NVD of the contralat-
eral ICA
Ophthalmic artery
obstruction with
no carotid artery
disease (1 eye)
1984 Sturrock and 7 (7) Blurred vision 20/20--HM Conjuctival and Narrowed RA Stenosis or HTA (57%)
Mueller or VL (6/7) episcleral Dilated RV, RH occlusion of DM (14%)
Orbital pain injection MA, telangiectasias ipsilateral CAD (14%)
(1/7) Corneal edema Cherry-red spot ICA or CCA IHD (14%)
Asymptomatic Descemet’s folds NVE, NVD (þ) Branchioce- Previous CI or TIA
(1/7) Bullous Spontaneous phalic artery (57%)
keratopathy, CRA pulsations occlusion Peripheral vascular
Mature cataract (1/7) disease (14%)
INV, NVG, (þ) Subclavian
hyphema artery occlusion
Anterior uveitis (1/7)
(cells, flare, KP)
Posterior synechia
Uveal ectropion
1985 Coppeto et al 2 (2) Blurred vision 20/40--LP Aqueous cells and Narrowed RA, 95% ipisilateral HTA (2/2)
(1/2) flare CRA pulsations ICA stenosis DM (2/2)
Ocular pain INV, PAS, NVG Optic disk cupping Previous cerebral
(2/2) Angle closure ischemic episode

MENDRINOS ET AL
(1/2)
1985 Jacobs and 6 (9) Blurred vision 20/40--CF Episcleral injection Dilated RV, BRAO Occlusion or HTA (83%)
Ridway or gradual Anterior uveitis RH, MA, CW spots stenosis (degree DM (33%)
VL (7/9) INV, NVG NVD, VH not specified) CAD (33%)
History of PAS, iris atrophy of ipsilateral Previous CVA or
TVL (5/9) ICA or CCA TIA (67%)
 Positive scotomata Fixed semi-dilated

OCULAR ISCHEMIC SYNDROME

(coloured or pupil
bright lights)
(5/9)
Ocular pain
(3/9)
1986 Brown 6 (7) VL 20/25-- INV Narrowed RA, $90% ipsilateral HTA (100%)
20/200 MA, RH ICA or CCA DM (17%)
Macular edema stenosis Previous CVA
(FA) (17%)
NVD
1986 Brown et al 35 (40) Not reported Not reported INV (70% of Narrowed RA, RH Overall a $ 80% DM (37%)
the eyes) NVE, NVD, VH ipsilateral ICA
AC flare or CCA stenosis
was present
1988 Brown and 43 (51) Gradual VL 20/20--20/40 INV (67% of Narrowed RA Overall a $ 80% HTA (56%)
Magargal (79% of the (35% of the the eyes) Dilated RV, MA, ipsilateral ICA DM (44%)
patients) eyes) NVG (35% of RH or CCA stenosis Atherosclerotic
Sudden VL (12% $ 20/400 the eyes) Cherry-red spot, was present CVD (35%)
of the patients) (65% of the Anterior uveitis CW spots, CE 1 patient had OIS Previous CVA or
No VL (9% of the eyes) (cells, flare, KP) Spontaneous caused by TIA (26%)
patients) CF or worse CRA pulsations ophthalmic
History of TVL (35% of the NVE, NVD, VH artery
(9% of the eyes) AION obstruction
patients)
Ocular/orbital
pain (40% of
the patients)
1989 Kerty 4 (4) Blurred vision 14/20--LP Episcleral injec- Narrowed RA Vary from HTA (100%)
and Eide or VL (4/4) tion, Corneal CRA pulsations occlusion DM (25%)
History of TVL edema CW spots, RH or O 75% Previous CI or TIA
(3/4) INV, NVG NVE, NVD, VH stenosis of the (100%)
Ocular pain PAS, aqueous flare Optic disk cup- ipsilateral ICA or Peripheral vascular
(2/4) ping, pallor CCA to occlu- disease (25%)
sion of both
ICAs
1989 Dhooge 8 (12) Gradual VL O 12/20--LP Episcleral injection Narrowed RA Occlusion HTA (63%)
and De (7/12) Corneal edema Dilated RV, RH or O 80% DM (25%)
Laey Sudden VL Anterior uveitis CW spots, CE stenosis of
(2/12) (flare, cells, KP) Spontaneous CRA ipsilateral ICA
Ocular pain INV, NVG, pulsations or CCA
(2/12) hyphema Cherry-red spot
Fixed semi-dilated NVE, NVD
pupil AION
Iris atrophy

11
(continued)
TABLE 3 (Continued)

12
Ophthalmic Findings at Initial Presentation

Surv Ophthalmol 55 (1) January--February 2010

No. of
Patients Visual Anterior Segment Posterior Carotid or Other Systemic Associations
Year Author (eyes) Symptoms Visual Acuity Signs Segment Signs Artery Disease (No. or% of patients)

1989 Wiebers 4 (8) Bilateral light- Normal--5/20 None Dilated RV Bilateral ICA high- HTA (2/4)
et al induced TVL RH, CW spots grade stenosis Previous CEA (1/4)
or occlusion Previous CI (1/2)
1989, Sivalingam 52 (60) Not reported 20/20--20/50 INV (62% of Narrowed RA Overall a $ 90% HTA (73%)
1991 et al (43% of the the eyes) Dilated but not ipsilateral ca- DM (56%)
eyes) NVG (22% of tortuous RV rotid IHD (48%)
20/60--20/400 the eyes) Dot and blot RH artery stenosis Previous CVA (27%)
(20% of the Anterior uveitis CW spots was present Peripheral vascular
eyes) NVE, NVD disease (19%)
CF or worse
(37% of the
eyes)
1990 Bolling and 3 (5) Gradual VL 20/20--LP INV, ANV, NVG Arteriovenous Vary from HTA (1/3)
Buettner (3/6) PAS communications ipsilateral CCA DM (2/3)
History of TVL Narrowed RA occlusion with
(1/6) Dilated RV high-grade
Light-induced TVL CW spots, MA, RH contralateral
Photophobia Optic disk atrophy carotid artery
(1/6) stenosis to
Ocular pain bilateral ICA
(2/6) occlusion
1992 Ho et al 11 (16) Blurred vision 20/20--no LP INV Narrowed RA Occlusion HTA (36%)
or VL (7/16) Aqueous cells Dilated RV, RH or $ 70% DM (45%)
Coloured or and flare CRVO, macular stenosis of the Previous MI (18%)
flickering edema ipsilateral ICA Previous CI ot TIA
lights (2/16) NVD, optic disk (36%)
History of TVL pallor
(1/16)
Ocular pain
(2/16)

MENDRINOS ET AL
Asymptomatic
(5/16)
1992 Hamed et al 4 (5) VL (5/5) 20/300--LP Corneal edema, CW spots, RH 20% ICA stenosis Giant cell arteritis
History of TVL Descemet’s folds Pallid optic (2/5)
(2/5) Unreactive pupil disk swelling
Diplopia (1/5) to light, RADP
Ocular hypotony
 OCULAR ISCHEMIC SYNDROME
Pain on eye Ptosis, limited
mouvement oculomotricity
(1/5)
Headache (2/5)
1995 Kerty et al 45 (45) Gradual VL 20/20--20/40 Episcleral injection Narrowed RA Occlusion HTA (29%)
(2/45) to no LP Aqueous cells and Dilated RV, RH or O 75% Abnormal neurologic
History of TVL flare CE, CRAO stenosis of examination (not
(19/45) INV, NVG NVE, NVD ipsilateral ICA specified) (36%)
Exercise or bright Impaired pupil Optic disk atrophy
light-induced reaction
TVL
Periorbital pain
(9/45)
1997 Mizener 32 (39) Sudden VL $ 20/40 (15% Conjuctival Narrowed RA, Vary from mild HTA (50%)
et al (41% of the of the eyes) injection RH, NVE, NVD stenosis (! DM (56%)
eyes) 20/50--20/300 Corneal edema Blood column 50%) of the ipsi- CAD (38%)
Gradual VL (28% (21% of INV, ANV segmentation lateral ICA to bi- Previous CI or TIA
of the eyes) the eyes) PAS in vessels lateral 100% ICA (31%)
TVL (15% of # 20/400 (64% Asymetric Embolic plaques occlusion
the eyes) of the eyes) cataract Cherry-red spot Occlusion or se-
Ocular/orbital CRA pulsations vere stenosis
pain CRVO, optic disk (80--99%) of the
(13% of the edema, cupping, ipsilateral ICA
eyes) pallor was present in
Asymptomatic Choroidal 74% of the eyes
(21% of the infarction
eyes)
1997 Levin and 2 (2) Postprandial TVL 20/50--20/30 Conjuctival RH 90% ipsilateral ICA HTA (2/2)
Mootha (2/2) injection stenosis þ 50% DM (1/2)
TVL after postural contralateral CAD (1/2)
change (1/2) carotid siphon Hypercholesterolemia
Positive scotomata stenosis (1/2) (1/2)
(bright lights) Ipsilateral ICA
(1/2) occlusion þ 40--
70% contralat-
eral ICA stenosis
(1/2)
1999 Kawaguchi 32 VL (24/32) Not reported INV CW spots, RH Occlusion of ICA Not reported
et al History of TVL NVD
(1/32)
VL þ history of
TVL (7/32)

(continued)

13
TABLE 3 (Continued)

14
Ophthalmic Findings at Initial Presentation

Surv Ophthalmol 55 (1) January--February 2010

No. of
Patients Visual Anterior Segment Posterior Carotid or Other Systemic Associations
Year Author (eyes) Symptoms Visual Acuity Signs Segment Signs Artery Disease (No. or% of patients)

1999 Inoue 23 (25) VL (23/25) 20/20--no LP INV Dilated RV, RH Occlusion HTA (52%)
History of TVL CRAO, BRVO, or $ 60% DM (100%)
(3/25) CE NVE carotid artery CAD (13%)
AION, PION, stenosis Previous CVA
optic disk or TIA (39%)
atrophy Peripheral vascular
disease (26%)
1999 De Graeve 2 (4) VL (2/4) Normal--CF INV Dilated RV, RH, Range from high- DM (1/2)
et al Macular edema grade ipsilateral Hypercholesterolemia
Peripheral CCA stenosis
vascular to bilateral CCA
occlusions, CW occlusion
spots
NVE, VH
2005 Alizai et al 2 (3) Blurred vision 20/100--LP INV Ischemic retinal Bilateral ECA HTA (2/2)
and visual loss Sluggish pupil edema, RH occlusions DM (1/2)
(2/2) reaction to Pallid optic disk Hyperlipidemia (1/2)
Periocular pain light swelling Peripheral vascular
(1/2) RADP disease (1/2)
Previous CEA (1/2)
2007 Amselem 2 (4) Sudden VL 20/40--HM Corneal edema Macular edema Vary from 75% Not reported
et al (2/4) AS inflammation Capillary non- carotid artery
Ocular pain INV, posterior perfusion stenosis to
(1/4) synechia occlusion
AC 5 anterior chamber; AION 5 anterior ischemic optic neuropathy; ANV 5 angle neovascularization; AS 5 anterior segment; BRAO 5 branch retinal artery occlusion;
BRVO 5 branch retinal vein occlusion; CAD 5 coronary artery disease; CCA 5 common carotid artery; CE 5 cholesterol emboli; CEA 5 carotid endarterectomy;
CF 5 counting fingers; CI 5 cerebral infarction; CRA 5 central retinal artery; CRAO 5 central retinal artery occlusion; CRVO 5 central retinal vein occlusion;
CVA 5 cerebrovascular accident; CVD 5 cardiovascular disease; CW 5 cotton-wool; DM 5 diabetes mellitus; ECA 5 external carotid artery; FA 5 fluorescein angiography;
HM 5 hand motions; HTA 5 hypertension; ICA 5 internal carotid artery; IHD 5 ischemic heart disease; INV 5 iris neovascularization; KP 5 keratic precipitates;
LP 5 light perception; MA 5 microaneurysms; MI 5 myocardial infarction; NVD 5 new vessels on the disk; NVE 5 new vessels elsewhere; NVG 5 neovascular glaucoma;

MENDRINOS ET AL
PAS 5 peripheral anterior synechia; PION 5 posterior ischemic optic neuropathy; RA 5 retinal arteries; RADP 5 relative afferent pupillary defect; RH 5 retinal
hemorrhages; RV 5 retinal veins; TIA 5 transient ischemic attack; TVL 5 transient visual loss; VH 5 vitreous hemorrhage; VL 5 visual loss.
OCULAR ISCHEMIC SYNDROME
filling, the posterior watershed zone located be-
tween the optic disk and the macula persists for
a longer time compared to normal eyes and is
observed as a dark hypofluorescent zone (Fig. 6).
Delayed filling or occlusion of the choriocapillaris in
the peripheral watershed zones can also be
observed.
C. ELECTRORETINOGRAPHY
The b wave of the electroretinograph (ERG)
corresponds to activity of Müller and/or bipolar
cells and reflects the functional status of the inner
retinal layer, whereas the a wave corresponds to
activity of photoreceptors.34,101 In CRAO, where
there is ischemia of the inner retina, the amplitude
of the b wave is decreased.30 In eyes with OIS, where
both the retinal and the choroidal circulation are
compromised, there is ischemia of the inner and
outer retina that results in decreased amplitude of
both a and b waves.29 Reduction in the amplitude of
the oscillatory potential of the b wave has been
demonstrated in eyes with carotid artery stenosis
even if the fluorescein angiography is normal.51
Carotid artery reconstructive surgery increases
ocular blood flow leading to better retinal function
and may increase in that way the amplitudes of a and
b waves of the ERG.226
D. VISUAL-EVOKED POTENTIALS
Visual-evoked potentials (VEP) after exposure to
intense light stimulation (photostress) show an
increase in latency and a decrease in amplitude.
Photostress induces transient VEP changes consist-
ing of an increase in response latency and a decrease
in amplitude. When serial VEP recordings are
obtained at discrete time intervals after bleaching,
the recovery of the VEP waveform can be evaluated.
The time it takes the VEP to recover to the baseline
status (recovery time after photostress) ranges in
normal subjects between 68 and 78 seconds.195 The
recovery time after photostress is prolonged in
patients with severe carotid artery stenosis and
improves following endarterectomy and extracra-
nial--intracranial (EC-IC) arterial bypass sur-
gery.13,77,128 The VEP may elicit visual dysfunction
at a stage where ophthalmological changes are
absent or minimal and may be useful for the
investigation of patients with carotid occlusive
disease.78
E. OPHTHALMODYNAMOMETRY
Ophthalmodynamometry is used to estimate the
pressure in the OA, approximatively at the site of
origin of the CRA. In the 1970s, ophthalmodyna-
mometry was used for the diagnosis of carotid artery
15
diseases. Measurements were performed by increas-
ing IOP by gradually applying pressure to the globe
and observing the arteries on the optic disk with
a direct or an indirect ophthalmoscope until they
begin to pulsate.60,150,220 The pressure required to
produce artery pulsations on the optic disk reflects
OA diastolic pressure, whereas the force required to
cause cessation of arterial pulsations reflects OA
systolic pressure.60,149,220,253,258 In OIS, the CRA
perfusion pressure is low and for this reason the
pressure necessary for the pulsations to appear is
reduced. Diastolic are considered to be more
reliable than systolic readings 220 and are decreased
in OIS,122 and may improve or return to normal
after carotid artery surgery.133 A recent ophthalmo-
dynamometric device consists of a conventional
Goldmann contact lens with a pressure-sensor in
its mounting support.122
F. OCULAR PLETHYSMOGRAPHY
Ocular plethysmography is another non-invasive
method for detection of carotid occlusive disease. It is
capable of detecting hemodynamically significant
carotid stenosis with an accuracy of 90% or
more.12,170,202 It measures indirectly the OA pressure
by recording variations in the size/volume of the
eyeball or ocular pulsations. These latter depend on
ocular perfusion pressure which in turn depends in
part on IOP. Intraocular pressure elevation above the
systolic ophthalmic pressure results in total oblitera-
tion of the ocular pulsations. Maximum ocular
pulsations are noted when IOP approximates or is
somewhat lower than ophthalmic diastolic pres-
sure.83 The most commonly used ocular pneumo-
plethysmograph is the OPG-Gee, which produces
elevation of IOP by applicaction of a suction cap to
the sclera. As IOP decreases, ocular pulsations start to
appear. In carotid artery occlusive disease, the ocular
perfusion pressure is lower ipsilateral to the site of
occlusion, meaning that IOP has to be reduced low
enough before the first ocular pulsations to appear.
Consequently in unilateral or assymetric bilateral
occlusive disease, the first ocular pulsations are
recorded later and with reduced amplitude in the
eye with the more severe obstruction.83,170
Although of historic interest, both ophthalmody-
namometry and ocular plethysmography have been
replaced by carotid artery imaging methods in the
work-up of patients with carotid artery disease.
G. IMAGING METHODS FOR THE EVALUATION OF
CAROTID OCCLUSIVE DISEASE
1. Carotid Duplex Ultrasound
Duplex carotid ultrasonography is the most
commonly used non-invasive test and combines
 16
TABLE 4

Surv Ophthalmol 55 (1) January--February 2010

Case Reports on the Ocular Ischemic Syndrome: Summarized Data
Ophthalmic Findings at Initial Presentation
No. of
Patients Visual Anterior Segment Posterior Segment Carotid or Other
Year Author (eyes) Visual Symptoms Acuity Signs Signs Artery Disease Systemic Associations
1959 Vergez 1 (1) VL No LP Conjuctival Narrowed vessels, Presumed ICA HTA
Ocular pain injection RH occlusion with Previous CI
Corneal edema Retinal edema OA obstruction
AC fibrin Macular exudates (no imaging
Ocular hypotony Optic disk atrophy performed)
Ptosis
Ophthalmoplegia
Corneal
hypoesthesia
Fixed-dilated pupil
(orbital ischemia)
1963 Hedges 1 (1) Blurred vision 16/20 Not reported Dilated, sausage- Occlusion of ICA Previous cerebral
followed by VL shaped RV TIA followed by CI
Macular exudates,
RH
1972 Bullock et al 1(1) VL 20/400 Ciliary injection, Narrowed RA Occlusion of the HTA
Ocular pain Descemet’s folds Dilated RV, RH OA and severe Previous cerebral
Photophobia Aqueous flare and bilateral carotid TIA
cells, INV artery stenosis
Poor pupillary light
reaction
1976 Neupert >et al 1 (1) Blurred vision 16/20 None Dilated RV, 99% ipsilateral None
MA, RH ICA stenosis with
NVD contralateral ICA
occlusion
1983 Campo 1 (2) Blurred vision 20/50 None MA Bilateral CCA and Previous MI
and Reeser (2/2) Retinal capillary ICA occlusion Peripheral vascular

MENDRINOS ET AL
telangiectasias disease
Capillary non-
perfusion
1983 Kiser et al 1 (1) Gradual VL HM Conjuctival CRAO, spontaneous Ipsilateral ICA DM
History of TVL injection CRA pulsations occlusion
Periocular pain INV, NVG MA, RH
RADP
1984 Carter 1 (1) Gradual VL 20/20 None Narrowed RA, Ipsilateral CCA Previous cerebral TIA
History of TVL dilated RV occlusion Peripheral vascular

OCULAR ISCHEMIC SYNDROME

RH, Nerve fiber disease
layer
hemorrhages
Swollen optic disk
1986 Kahn et al 1 (2) Histrory of 20/30 Conjuctival Narrowed RA, Atherosclerotic HTA
TVL (2/2) injection dilated RV aortic arch Previous
Ocular pain (2/2) Aqueous flare, cells CW spots, RH syndrome cerebral TIA
Sluggish pupil
reaction to light
1988 Duker and 1 (1) TVL 20/50 INV, aqueous flare Narrowed RA, RH Ipsilateral ICA HTA
Belmont dissection CAD
1988 Wagner et al 1 (2) VL (1/2) 20/30--HM INV, NVG Narrowed RA, CW $95% bilateral ICA HTA
Ocular pain (1/2) Pupil abnormalities spots stenosis
1991 Bogousslavsky 1 (1) Sudden VL no LP Episcleral injection Retinal arterial Ipsilateral CCA None
et al Retroocular pain Corneal blood column occlusion
Diplopia hypoesthesia segmentation
Ptosis, severe Massive retinal
ophthalmoplegia edema, RH
Unreactive pupil Pallid optic disk
RAPD swelling
(orbital infarction)
1992 Bierly and 1 (1) VL CF Conjuctival Narrowed RA 90--95% ipsilateral DM
Dunn Ocular pain injection ICA stenosis Athelosclerotic
Striate keratopahty cardiac disease
Aqueous flare and Peripheral vascular
cells disease
1992 Daels et al 1 (2) Blurred vision 16/20--12/ INV Dilated RV, RH ICA occlusion on Previous CI
(1/2) 20 Semi-dilated pupil one side with 90%
ICA stenosis on
the other side
1996 Barrall and 1 (1) VL 20/100 Not reported Narrowed RA, ICA occlusion, Neurofibromatosis 1
Summers dilated RV moyamoya vessels Moyamoya disease
Arteriovenous
communications
NVE, NVD, VH
(Hamartoma of
the retina and
RPE)
1998 Flaxel et al 1 (2) VL 25/20--20/ None RH ICA occlusion on HTA
40 Fibrotic CNV one side with CCA
occlusion on the
other side

17
(continued)
TABLE 4 (Continued)

18
Ophthalmic Findings at Initial Presentation

Surv Ophthalmol 55 (1) January--February 2010

No. of
Patients Visual Anterior Segment Posterior Segment Carotid or Other
Year Author (eyes) Visual Symptoms Acuity Signs Signs Artery Disease Systemic Associations

1999 Hwang et al 1 (2) Sudden VL (1/2) 20/30--LP Conjuctival Swollen optic disk Mild to severe Giant cell arteritis
Blurred vision (1/2) injection Peripapillary bilateral ICA HTA
Corneal edema, hemorrhages stenosis Pernicious anemia
Descemet’s folds CW spots
AC flare
Ocular hypotony
Distorted pupil
RAPD
1999 Nehmad and 1 (1) Postprandial TVL 20/20 None Dilated RV, RH ICA occlusion HTA
Madonna DM
Hypercholesterolemia
2000 Hashimoto 1 (1) VL HM Episcleral injection Narrowed RA Bilateral ICA Not reported
et al Ocular pain NTG Optic disk cupping, occlusion
palor
2000 Gross 1 (1) VL 20/400 INV Narrowed RA, RH Ipsilateral ICA Hyperlipidemia
Trace RAPD occlusion
2001 Casson et al 1 (2) VL (2/2) no LP Corneal edema Swollen optic disk Not reported Giant cell arteritis
Ocular hypotony
2001 Karacostas 1 (2) Gradual VL HM INV, ANV Narrowed RA, Ipsilateral CCA HTA
et al History of TVL PAS, angle closure dilated RV occlusion CAD
Periorbital pain Fixed-dilated pupil MA, RH, optic disk
pallor
2001 Kaiboriboon 1 (2) Light-induced TVL 20/20-- None Dilated RV Left ICA occlusion None
et al (2/2) 20/30 with severe right
ICA and ECAs
stenoses
2001 Worrall et al 1 (2) Gradual VL (1/2) 20/20--20/ None Narrowed RA, Aortic arch Takayasu arteritis
Histrory of TVL 50 dilated RV syndrome

MENDRINOS ET AL
(1/2) CW spots, MA, RH
Ocular pain (1/2) Telangiectasias
2002 Ishikawa et al 1 (1) None 20/20 Not reported RH 90% ipsilateral ICA HTA
stenosis Previous cerebral TIA
2002 Rennie and 1 (1) VL 20/40 None RH, NVD Severe ipsilateral HTA
Flanagan ICA stenosis DM
Hypercholesterolemia
2002 Imrie et al 1 (2) Gradual VL (1/2) 6/9--6/36 INV Narrowed RA None Hyperhomocysteinemia
RADP MA, RH Raynaud’s

OCULAR ISCHEMIC SYNDROME

phenomenon
2002 Morales et al 1 (2) Gradual VL (2/2) 20/40--20/ Conjuctival Narrowed RA, Atherosclerotic aor- Previous cerebral TIA
History of TVL 200 injection dilated RV tic arch syndrome
(2/2) Aqueous flare and CW spots with severe CCA
cells stenosis on one
Sluggish pupil side
reaction to light
RADP
2003 Shortt et al 1 (1) VL CF Corneal edema, INV None Ipsilateral OA Dysthyroid?
Ocular pain AC inflammation obstruction as a
Lid retraction and result of thyroid
proptosis eye disease with
Ipsilateral RAPD enlargement of
the extraocular
muscles
2003 Védrine 1 (1) VL Not Corneal edema, AION Not reported Giant-cell arteritis
et al reported Descemet’s folds
Aqueous cells and
flare
Fixed semi-dilated
pupil
Ocular hypotony
Limited
oculomotricity
2004 Klais and 1 (1) VL 20/200 Not reported Narrowed RA, Possible ipsilateral Not reported
Spaide dilated RV OA stenosis
RH, CRA pulsations
Macular edema
Optic disk swelling
and hemorrhage
2006 Bigou 1 (1) Gradual VL 20/200 None Narrowed RA High-grade DM
et al Dilated RV, RH ipsilateral ICA Peripheral vascular
stenosis disease
Previous CI
2006 Konuk et al 1 (1) Sudden VL LP None Retinal edema, Ipsilateral ICA Scleroderma
History of TVL chery-red spot occlusion
CRAO
2006 Koz et al 1 (2) Gradual VL (2/2) 20/40 INV, ANV MA, NVD Aortic arch Takayasu arteritis
AC cells syndrome
2006 Schotveld 1 (1) Gradual VL 20/200 Scleral melting Macular and Ipsilateral ICA HTA
et al INV peripheral retina subocclusion DM
ischemia (FA) with contralateral CAD

19
ICA occlusion

(continued)
 20 Surv Ophthalmol 55 (1) January--February 2010 MENDRINOS ET AL

B-mode ultrasound and Doppler ultrasound within

LP 5 light perception; MA 5 microaneurysms; MI 5 myocardial infarction; NVD 5 new vessels on the disk; NVE 5 new vessels elsewhere; NVG 5 neovascular glaucoma;
PAS 5 peripheral anterior synechia; PION 5 posterior ischemic optic neuropathy; RA 5 retinal arteries; RADP 5 relative afferent pupillary defect; RH 5 retinal
CVA 5 cerebrovascular accident; CVD 5 cardiovascular disease; CW 5 cotton-wool; DM 5 diabetes mellitus; ECA 5 external carotid artery; FA 5 fluorescein angiography;
HM 5 hand motions; HTA 5 hypertension; ICA 5 internal carotid artery; IHD 5 ischemic heart disease; INV 5 iris neovascularization; KP 5 keratic precipitates;
CF 5 counting fingers; CI 5 cerebral infarction; CRA 5 central retinal artery; CRAO 5 central retinal artery occlusion; CRVO 5 central retinal vein occlusion;
AC 5 anterior chamber; AION 5 anterior ischemic optic neuropathy; ANV 5 angle neovascularization; AS 5 anterior segment; BRAO 5 branch retinal artery occlusion;
BRVO 5 branch retinal vein occlusion; CAD 5 coronary artery disease; CCA 5 common carotid artery; CE 5 cholesterol emboli; CEA 5 carotid endarterectomy;
Systemic Associations

Hypertriglyceridemia
a single instrument, providing both anatomical
imaging of the vessel and flow velocity informa-
tion.229 The parameters used to classify severity of
stenosis include peak systolic velocity (PSV), end-
diastolic velocity, and the ICA/CCA PSV ratio.
Compared to conventional intra-arterial digital
HTA
DM
substraction angiography (DSA) for detection of
high-grade symptomatic carotid artery stenosis,
duplex ultrasound (DUS) has a sensitivity of 89%
Carotid or Other

hemorrhages; RV 5 retinal veins; TIA 5 transient ischemic attack; TVL 5 transient visual loss; VH 5 vitreous hemorrhage; VL 5 visual loss.
and a specificity of 84%.244 For detecting occlusion,
90--95% bilateral
Artery Disease

ICA stenosis

DUS has a sensitivity of 96% and a specificity of

100%.181
Incomplete imaging of the carotid bifurcation,
because of a high bifurcation, a long (O3 cm) ICA
plaque, or calcific shadows, are the most common
reasons for inadequate duplex scans, followed by
MA, white-centered
Posterior Segment

borderline severe ICA disease, suspected extracer-

vical disease (supra-aortic trunk, vertebral, or in-
tracranial), ICA near-occlusion, and diffuse
Signs

recurrent stenosis.10 In addition, ultrasound is

limited if vessels are tortuous, ultrasound is opera-
RH

tor- and machine-dependent, and needs to be

Ophthalmic Findings at Initial Presentation

validated at each center if it is to be relied upon

for decision-making.3,165 Because of these limita-
Anterior Segment

tions, other non-invasive or minimally invasive

techniques are increasingly used supplementary to
Signs

DUS, as described in section X.G.3.

None

2. Color Doppler Imaging of Retrobulbar Vessels

Color Doppler imaging (CDI) of retrobulbar
vessels is a useful adjunct to conventional DUS for
6.0/15
Acuity
Visual
Visual Symptoms

Gradual VL
(2/2)
Patients
No. of

(eyes)

1 (2)
TABLE 4 (Continued)

Ho et al
Author

Fig. 2. Fluorescein angiography in ocular ischemic

syndrome. Notice the background choroidal patchy
hypofluorescence corresponding to a delayed filling of
some areas of the choriocapillaries layer and the
2008

characteristic leading edge of the dye in the retinal

Year

arteries (at 35 seconds).

OCULAR ISCHEMIC SYNDROME
Fig. 3. Fluorescein angiography in ocular ischemic
syndrome. Arterio-venous transit time is prolonged. At
77 seconds, the retinal arterioles are not completely filled
and the flow in retinal veins is still laminar.
carotid artery examination. It is a simple, reproduc-
ible and non-invasive tool for the study of retro-
bulbar hemodynamics.1,153,154,198 Distal to
a hemodynamic significant stenosis, the blood
pressure is decreased and the Doppler effect
becomes dampened, causing diminished blood flow
velocity. Therefore, studying the flow profile in the
OA, the CRA and the short posterior ciliary arteries
(SPCA) may provide hemodynamic information
about the carotid and retrobulbar circulations such
as velocities and pulsatility indices (an indicator of
vascular resistance) of the orbital arteries. These
parameters are significantly reduced in patients with
significant carotid artey stenoses as compared to
a normal, age-matched population with no carotid
disease.53,112,155
Fig. 4. Fluorescein angiography in ocular ischemic
syndrome. There is staining of both retinal veins and
arteries; retinal artery staining is more prominent than
retinal vein staining.
21
Fig. 5. Fluorescein angiography in ocular ischemic
syndrome. The mid-peripheral retina shows widespread
capillary drop-out.
CDI of retrobulbar vessels also allows studying the
flow direction in the OA (Fig. 7). Reversed OA flow
pattern is a highly specific indicator of ipsilateral
high-grade ICA stenosis or occlusion (Fig. 8) with an
excellent positive predictive value but with a moder-
ate negative predictive value (82%) and a limited
sensitivity (55%). This gives an overall accuracy of
85% for OA flow direction to indicate high-grade
ipsilateral ICA stenosis or occlusion.200 Several re-
searchers feel that flow reversal in the OA produces
a steal phenomenon from the ocular circulation to
the low pressure intracranial circuit, causing further
reduction in the retrobulbar blood flow and may lead
to development of OIS.54,104,113,138,139,151,203 Others
did not find significantly lower OA and CRA flow
velocities in patients with OIS than in patients with
high-grade carotid artery stenosis and no OIS and
could not demonstate OA flow reversal as a marker
for development of OIS.50,104,167
This discrepancy between studies concerning the
association of reversed OA flow with OIS may be
because OA flow patterns in patients with high-grade
carotid stenosis vary depending on the presence and
the type of collateral pathways, severity of stenosis,
and the presence of systemic disease, especially
ischemic heart disease and hypertension.79 Eyes with
a high reverse flow velocity in the OA may be at
greater risk for OIS,79 but OIS can also develop in eyes
with CRA and SPCA flow velocities that are markedly
diminished regardless of the OA flow direction.254
Anterograde OA flow may be preserved by adequate
collateral circulation via the circle of Willis in
22 Surv Ophthalmol 55 (1) January--February 2010
Fig. 6. Indocyanine green angiography in ocular ischemic syndrome. A: Choroidal hypofluorescence corresponding to
the main posterior watershed zone between the medial and lateral posterior ciliary arteries. B: Filling of the choroidal
watreshed zone is delayed, with some part of it remaining hypofluorescent 10 seconds later.
response to reduced inflow pressure in the distal
ICA,254 and reversal of flow may occur only under
certain conditions that further decrease blood
pressure in the head such as raising the arms.203
Finally, if the ICA stenosis is associated with stenosis or
occlusion of the ipsilateral ECA, the perfusion
pressure may become very low in the ECA and the
OA flow may be still anterograde.190
These findings highlight the importance of CDI
of the retrobulbar vessels for the identification and
follow-up of patients at risk for developing OIS, for
its diagnosis, and for the preoperative and post-
operative evaluation of patients with OIS.50,84,167,243
They also underline the dynamic nature of the
circulation and the advantage of CDI over invasive
carotid arteriography in understanding how the
circulation adapts.
Fig. 7. Transcranial color-coded duplex imaging (2 MHz
sector transducer): Doppler signal of a normal ophthal-
mic artery flow showing positive velocities. (Courtesy of
Dr. Fabienne Perren, MD, University Hospital and Medical
Faculty of Geneva, Department of Neurology, Neuro-
sonology Unit, Geneva, Switzerland.)
MENDRINOS ET AL
3. Minimally Invasive Methods (Magnetic
Resonance Angiography and Computed
Tomographic Angiography)
New non-invasive or minimally invasive methods,
and combinations of them, are increasingly used as
the second-line investigation tool after DUS for
carotid stenosis. Magnetic resonance angiography
(MRA) and computed tomographic angiography
(CTA) have gradually replaced DSA.
A systematic review of carotid MRA performance
data found that for the diagnosis of 70--99% carotid
stenosis, MRA had a pooled sensitivity of 95% and
a pooled specificity of 90% (compared to conven-
tional DSA).181 For detection of complete occlu-
sions, MRA yielded a sensitivity of 98% and
a specificity of 100%. Magnetic resonance angiogra-
phy has a better discriminatory power compared to
DUS in diagnosing 70--99% stenosis (Fig. 9). For
detecting occlusion, both DUS and MRA are very
accurate.181 Limitations of MRA include claustro-
phobia, pacemakers and metallic stents or implant-
able defibrillators, and obesity.
A systematic review on the diagnostic accuracy of
CTA for assessment of symptomatic carotid artery
disease reported pooled sensitivity and specificity for
the detection of 70--99% carotid stenosis (relative to
DSA) of 85% and 93%, respectively. The sensitivity
and specificity for detecting carotid occlusion were
97% and 99%, making CTA an accurate modality for
detection of severe carotid artery disease, particularly
for detection of occlusions.145 A similar systematic
review reported slightly better results with pooled
CTA sensitivity of 95% and pooled specificity of 98%
in the detection of 70--99% carotid stenosis.109
Interest in CTA has been renewed with the advent
of multi-slice detectors CT scanners and improved
OCULAR ISCHEMIC SYNDROME
Fig. 8. Transcranial color-coded duplex imaging (2 MHz
sector transducer): Doppler signal of an inverted oph-
thalmic artery flow in a case of high grade internal carotid
artery stenosis (95%) showing negative velocities (in-
version). (Courtesy of Dr. Fabienne Perren, MD, Univer-
sity Hospital and Medical Faculty of Geneva, Department
of Neurology, Neurosonology Unit, Geneva, Switzerland.)
software for 2-D and 3-D reconstructions
(Fig. 10).61,127,166,210 Inherent advantages compared
to single-slice CT scanners include better spatial
resolution, superior contrast resolution, and speed,
but substantial data of their performance are still
lacking.70 Disadvantages of CTA are the necessity of
administrating a nephrotoxic iodinated contrast
agent and ionizing radiation and/or artifacts related
to heavily or circumferentially calcified arterial walls.
Both MRA and CTA are still evolving and
improving and comparisons between non-invasive
imaging modalities may change. Contrast (gadoli-
nium)-enhanced MRA (CE-MRA) has less signal loss
from turbulent flow near stenoses and less move-
ment-related artefacts than non-contrast time of
flight MRA, is more rapid, produces images with
higher spatial resolution, and allows visualization of
the vasculature from the aortic arch up to the circle
of Willis.48,205 The most recent meta-analysis by
Wardlaw et al found that CE-MRA was more sensitive
for 70--99% symptomatic carotid artery stenosis than
DUS, MRA, and CTA. This latter had the highest
specificity, followed by CE-MRA, DUS, and MRA.244
Potential advantage of MRA and CTA over conven-
tional angiography is their ability to allow better
carotid plaque characterization and identification of
a vulnerable plaque61,74,93,179,185,208,209,251,256,257 as
well as to provide simultaneous information about
the brain parenchyma before surgery, especially
critical for patients with recent transient symp-
toms.159 Recent advances in both techniques allow
evaluation of the intracranial atherosclerotic steno-
occlusive disease16,44,85,100,241 and may become cost-
effective techniques for the preoperative evaluation
of patients with carotid occlusive disease.245
23
In addition, combined use of MRA, CTA, and
DUS improves diagnostic accuracy for high-grade
symptomatic carotid stenoses and minimizes the
need for invasive carotid arteriography in patient
selection for carotid artery endarterectomy (CEA) in
cases where results of DUS alone are indeterminate
or inadequate.10,11,102,157,181,186,196,215,232,233
4. Carotid Arteriography
Conventional intra-arterial digital substraction
angiography has long been considered as the gold
standard for imaging the cerebrovascular system
and was the technique used to assess carotid stenosis
and select patients for surgery in multicenter
trials.72,187 Nevertheless, it is not ideal for screening
and follow-up both because of the risks of disabling
cerebral infarction and systemic complications and
also because of its high cost. In patients with
arteriosclerosis, a 4% risk of transient ischemic
attack or minor cerebral infarction, a 1% risk of
major cerebral infarction, and even a small (less
than 1%) risk of death have been reported.58,92 The
cerebral infarction rate from cerebral arteriography
in the Asymptomatic Carotid Atherosclerosis Study
was 1.2% and accounted for about one-half of the
23% cerebral infarction rate in the surgical treat-
ment group. It is important to note that in patients
with OIS, who have poor collateral circulation and
severe carotid artery disease, arteriography-related
risks may be even higher.
To summarize, DUS should be chosen as the first-
line investigation of patients suspected of having
carotid stenosis. If surgically significant stenosis is
identified or in equivocal cases, further imaging
with either CE-MRA or CTA is required. If the
results of both tests agree, carotid arteriography may
be omitted. If results are contradictory or inconclu-
sive, conventional DSA should be the final arbiter.
XI. Management of Ocular Ischemic
Syndrome
The management of OIS is multidisciplinary,
involving the ophthalmologist, cardiologist, neurol-
ogist, vascular surgeon, neurosurgeon, and some-
times the rheumatologist and interventional
neuroradiologist. The aim is to treat the ocular
complications and prevent further ocular damage,
to investigate and treat the associated vascular risk
factors, and to perform surgery whenever indicated.
A. OCULAR TREATMENT
The ocular treatment is directed toward control of
anterior segment inflammation, ablation retinal
ischemia, and control of increased IOP and of
24 Surv Ophthalmol 55 (1) January--February 2010 MENDRINOS ET AL

Fig. 9. 3D- reconstructed magnetic resonance angiography in carotid artery disease. A: High-grade stenosis of the left
internal carotid artery origin (arrow) in a 58-year-old diabetic woman. B: Severe bilateral stenosis at the origin of the
internal carotid arteries (arrows) in a 48-year-old woman.

neovascular glaucoma.41,162 Topical therapy includes
steroids to suppress anterior segment inflammation,
and long-acting cycloplegic agents to stabilize the
blood--aqueous barrier and limit iris movement in
order to decrease the likelihood of spontaneous
hyphema. Medical treatment of increased IOP con-
sists of ocular hypotensive agents that reduce aqueous
outflow, namely, topical b-adrenergic blockers, or a-
agonists (that also increase uveoscleral flow), along
with topical and/or oral carbonic anhydrase inhibi-
tors. Prostaglandins should be avoided whenever
possible because they increase ocular inflammation.

Fig. 10. Computed tomographic angiography in carotid artery disease. A: Note the stenosis of the left internal carotid
artery (arrow). B: 3D reconstructed image of the same patient.
OCULAR ISCHEMIC SYNDROME
Pilocarpine and other anticholinergic agents are
generally contraindicated because they may also
increase inflammation and cause miosis. Moreover,
pilocarpine acting on the outflow pathway is not
effective in eyes with angle neovascularization.
When neovascular glaucoma develops, IOP control
is usually refractory to medical therapy and surgery or
cycloablation is often needed. Currently, trabeculec-
tomy with antimetabolites, aqueous shunt implants,
or diode laser cyclophotocoagulation are the pre-
ferred treatment options.221 In patients with useful
vision or potential for visual recovery where there is
regression of iris or angle neovascularization follow-
ing peripheral retinal ablation, trabeculectomy with
antimetabolites is often the preferred surgical ap-
proach but is associated with a high failure rate. In
failed trabeculectomy cases or when there is active
anterior segment neovascularization, aqueous shunt
implants are an alternative option. In patients with no
useful vision and in pain who are thought to have
limited or no potential for visual recovery, cyclo-
ablation is preferable to invasive surgery. If the eye
remains painful, retrobulbar injection of alcohol or
chlorpromazine may provide relief. If these fail to
alleviate pain in a blind eye, enucleation or eviscer-
ation should be considered.221
Panretinal photocoagulation (PRP) may be effec-
tive in same patients with ocular neovascularization
caused by carotid occlusive disease (Fig. 11) and
may prevent development of neovascular glau-
coma.36,42,119,222 If the fundus is not visible due to
media opacities or poor pupillary dilation and it is
not possible to perform adequate PRP, other
modalities should be considered, including 360#
transconjunctival cryotherapy in the mid-peripheral
and peripheral retina and transscleral diode laser
retinopexy.89,140,206,221
Panretinal photocoagulation causes regression of
iris neovascularization in only 36% of the treated
eyes with OIS.222 It is important to note that there
may be no signs of capillary-dropout in the
fluorescein angiograms of patients with OIS and
neovascularization, even in those with co-existant
diabetes mellitus.176 Even if adequate PRP is applied
to existing areas of retinal ischemia, posterior
segment neovascularization may still develop or get
worse.234 This suggests that uveal ischemia alone
with no retinal ischemia may be sufficient to induce
neovascularization, as this has been experimentally
induced in animal studies.96 If there is no evidence
of retinal ischemia in the form of capillary non-
perfusion, then there is no scientific rationale to
recommend PRP.162 In such cases of uveal ischemia
rather than retinal ischemia, the adverse effects of
PRP such as pain and further visual field constric-
tion are to be avoided.
25
Intravitreal antivascular endothelial growth factor
and triamcinomlone have been used in the treat-
ment of iris neovascularization and macular edema
complicating OIS. Intravitreal bevacizumab has
been reported in two patients with OIS and iris
neovascularization, that regressed one week follow-
ing treatment.5 One eye developed recurrence of
iris neovascularization and was reinjected with no
further recurrence at the 7- month follow-up visit.
No changes were noted in visual acuity or IOP.
Macular edema may complicate OIS and may
further accentuate visual loss. The use of intravitreal
triamcinolone acetonide has been described in one
patient with cystoid macular edema and OIS. There
was resolution of edema and concomittant improve-
ment in visual acuity but the patient needed
repeated injections.141 Intravitreal bevacizumab has
also been used for the treatment of macular edema
in a patient with OIS. One week after injection,
macular edema regressed partially but with no
change in visual acuity.5 Further studies with longer
follow-up are needed to determine the role of
intravitreal steroids and anti-vascular endothelial
growth factors in patients with OIS complicated by
macular edema or neovascularization.
B. MEDICAL TREATMENT
The ophthalmologist should refer OIS patients to
a primary care physician and/or neurologist for full
medical and neurological assessment. Given the
high rate of vascular death (usually from myocardial
infarction), it is essential to treat associated systemic
diseases. Therapeutic options include antiplatelet
agents, treatment of hypertension, diabetes mellitus,
dyslipidemia, or coronary artery disease, as well as
cessation of smoking and weight reduction.86
When a specific disease is considered to be
responsible for OIS, then it should be treated. The
case of a patient presenting with OIS and no carotid
artery stenosis, thromboembolism, or vasculitis has
been reported. Vasospasm was believed to be the
cause of OIS and the patient was treated with
verapamil, a calcium channel blocker, and the
episodes of transient visual dimming ceased, VA
improved, iris neovascularization regressed, and
hypotony reversed.249
C. SURGICAL TREATMENT
1. Carotid Artery Endarterectomy
Large, randomized clinical trials from the early
1990s have shown the superiority of CEA and aspirin
therapy in preventing stroke compared with aspirin
therapy alone for both symptomatic14,71,72,168,187
and asymptomatic73,90,106 carotid artery stenosis.40,86
Based on these trials, the American Academy of
26 Surv Ophthalmol 55 (1) January--February 2010 MENDRINOS ET AL

Fig. 11. Panretinal photocoagulation (PRP) in ocular ischemic syndrome. New vessels on the disk in a patient with
occlusion of the internal carotid artery. A: Fundus color photograph shows the laser spots following PRP. B: leading to
regression of neovascularization.Optic disk cupping developped due to increased intraocular pressure (IOP) related to
neovascular glaucoma. A filtering surgery was performed sucessfully in order to reduce IOP. C: Notice the appearence of
hemorrhage on the optic disk suggesting progression of the ischemic process despite IOP within the normal limits
following surgery.

Neurology and the American Heart Association/
American Stroke Association recommend CEA for
symptomatic stenosis of 50--99% if the perioperative
risk of stroke or death is less than 6%.40,86 In
asymptomatic patients, CEA is recommended for
a stenosis of 60--99% if the perioperative risk of
stroke or death is less than 3%.86
The effect of CEA on the clinical signs and the
retrobulbar circulation of patients with OIS have
been investigated by several authors. Costa et al
analyzed prospectively the effects of CEA on the
retrobulbar circulation of 17 patients with severe
occlusive carotid artery disease using CDI.55 They
found improvement in the ipsilateral retrobulbar
blood flow following CEA and resolution of clinical
ophthalmoscopic findings. Kawagushi et al reported
similar results after examining 11 patients with OIS
from ICA stenosis (O70% stenosis) treated by
CEA.129 After a mean follow-up of 32 months, VA
had improved in five patients and the remainder six
patients showed no further visual loss. No patients
complained of recurrent visual symptoms during
the follow-up period. Similar results have been
reported by other authors, suggesting that CEA is
effective in reversing or preventing the progression
of chronic ocular ischemia or in increasing ocular
blood flow.47,49,50,84,117,148,167,184,199,201,207,212,226
On the contrary, Sivalingam et al could not
demonstrate a beneficial effect of CEA on visual
outcome in 17 eyes with OIS.222 At 1-year follow-up,
7% of the eyes showed improved VA, 33% remained
stable, and 60% showed further visual loss despite
surgery. Mizener et al, similarly, found no significant
difference in the visual outcome between patients
who underwent CEA and those who did not.176
However, the eyes included in these two last
studies had poor initial VA and most had iris
neovascularization or neovascular glaucoma, con-
trary to the studies that showed restoration or
stabilization of vision. The presence of iris neo-
vascularization implies a greater degree of ocular
ischemia and damage, making reversal of ischemia
and visual recovery unlikely and limiting any
beneficial effect of CEA on VA. Clearly, CEA is most
beneficial for the treatment of ocular ischemia if
performed early before neovascular glaucoma
develops.95,207 In 18 patients with OIS and after
a mean follow-up period of 21 months, visual acuity
improved or stabilized in 94.4% of the patients and
funduscopic ischemic signs improved or resolved in
93.3% of the patients following CEA.207
2. Carotid Artery Stenting
Carotid artery stenting (CAS) has emerged as
a treatment alternative in patients who need CEA.
Although endovascular treatments are an estab-
lished therapeutic modality for peripheral and
coronary arterial disease, there is still insufficient
evidence to support the use of CAS over CEA as the
treatment for carotid artery stenosis.68 To date, no
specific data exist on the effect of CAS for the group
of patients that was included in the randomized
trials of CEA versus medical therapy. CAS has been
used for patients who are considered to be at high-
risk for complications after CEA and who would
have been excluded from CEA trials.39,180 Anatomic
conditions that render surgery technically difficult,
such as previous neck irradiation or radical neck
surgery, recurrent stenosis after CEA, contralateral
recurrent laryngeal-nerve palsy, tracheostomy, and
high (beyond the second cervical vertebral level)
carotid stenosis, are good indications for CAS.39,180
Medical conditions that increase the risk of surgery,
such as unstable angina, recent myocardial infarc-
tion, multivessel coronary disease, congective heart
OCULAR ISCHEMIC SYNDROME
failure, are also appropriate indications for CAS, as
patients with these risk factors may be at lower risk
of cardiac morbidity with CAS when compared to
CEA.39,180 A number of clinical trials are ongoing
and will likely provide additional evidence to
support treatment choices for carotid artery
stenosis.
The effect of CAS in patients with OIS has been
studied, but available studies lack adequate sample
sizes and follow-up periods. This procedure has been
shown to normalize the disturbed OA flow, whether
this is reversed or antegrade, to improve OIS-related
symptoms and signs and to prevent its onset or
progression in patients with ICA stenosis of more
than 80% at its origin.130 Similar results have been
reported in patients with OIS from severe intracranial
carotid artery stenosis164 and in isolated cases of
OIS.105,189,191 Additional studies are needed to better
elucidate the role of CAS in the treatment of OIS.
3. Extracranial--Intracranial Arterial Bypass
Surgery
EC-IC bypass surgery is the surgical anastomosis of
the superficial temporal artery with a branch of the
middle cerebral artery and may be considered when
there is complete occlusion of the ICA or the CCA
or when ICA stenosis is inaccessible (at or above the
C2 vertebral body) to CEA.228 The aim of this
surgery is to increase cerebral blood flow and
prevent the development of cerebral ischemia.
The International Cooperative Extracranial--In-
tracranial Bypass Study, a multicenter randomized
trial that started in 1977, failed to show a beneficial
effect in preventing cerebral ischemia, with patients
undergoing surgery having cerebral infarctions
earlier and more frequently than patients receiving
medical treatment only.230 This trial has been
criticized6,7 and some neurosurgical centers contin-
ued to perform EC-IC bypass surgery on selected
cases. The patients who are most likely to benefit
from this procedure are those with persistent
ischemic symptoms refractory to maximal medical
therapy and with compromised cerebrovascular and
metabolic reserve capacity due to insufficient
collateral circulation. In such cases, the results seem
to be satisfactory both anatomically and
functionally.2,173,182,188,213,231
Several studies have investigated the effect of EC-
IC bypass surgery in eyes with OIS.
Kearns et al, in their series of 72 patients with ICA
who underwent EC-IC bypass, observed a slight
increase of CRA pressure with resolution of clinical
signs and symptoms, including ischemic pain, in
some of the patients.133 Similar results have been
reported subsequently.69,128,131--133,136,140,171,217
27
Nonetheless, in a smaller series of 13 patients by
Sivalingham et al, VA remained stable in 23% of the
eyes and 77% of the eyes showed progression of visual
loss after one year of follow-up, mostly from severe
ocular ischemia.222 There is still insufficient evidence
about the role of EC-IC bypass surgery in OIS.
A review of the current literature on the effect of
surgery in OIS suggests that CEA usually improves
ocular hemodynamic parameters, but stabilization
or improvement in vision seems to occur only when
performed early before development of iris neo-
vascularization or neovascular glaucoma. Carotid
endarterectomy is also benecifial in preventing
cerebral infactions. Carotid artery stenting and EC-
IC bypass surgery have emerged as alternatives to
CEA in selected patients and sometimes may be the
only possible surgical treatment modalities, but
their effect on OIS still needs further investigation.
We recommend a multidisciplinary approach when
considering surgery in patients with OIS, and we
suggest that such a decision be individualized.
XII. Visual Prognosis
Sivalingham et al investigated the visual prognosis
in 60 consecutive eyes with OIS.222 On initial
presentation, 43% of the affected eyes had a VA of
20/20--20/50, whereas 37% had VA of counting
fingers or worse. By the end of 1 year, 58% of the
eyes progressed to counting fingers or worse, only
24% had a VA of 20/20--20/50 and 18% had a VA of
20/60--20/400 despite treatment; 27% of all eyes
ended-up with bare light perception by the end of
one year and none of the eyes that presented with
VA of counting fingers or worse showed any
improvement. It should be noted that 62% of the
eyes presented initially with iris neovascularization.
Its presence is associated with a poor visual outcome
as 97% of those eyes had a final VA of counting
fingers or worse.
Visual acuity at presentation is another significant
predictor factor of visual prognosis. Mizener et al
showed that patients whose initial VA was $ 20/80
were more likely to preserve this level of VA, and
patients whose initial VA was # 20/400 tended to be
stable or worsen. No eye with an initial VA ! 20/400
had vision better than counting fingers after
a median follow-up of 1 year.176
XIII. Mortality
The mortality rate for patients with OIS is 40% at
5 years. The leading cause of death is cardiovascular
disease, usually myocardial infarction. This accounts
for about two-thirds of deaths. Cerebral infarction is
28 Surv Ophthalmol 55 (1) January--February 2010
the second leading cause of death (19%). By
comparison, an age- and sex-matched control
control group from the Framingham study had
a 5-year mortality of 11%.223 Given this high rate of
mortality in patients with OIS, it is essential that
physicians adopt appropriate therapeutic options
aiming at primary prevention of myocardial and
cerebral infarction.86
XIV. Summary and Conclusions
The ocular ischemic syndrome is a rare, but vision-
threatening, condition usually associated with severe
carotid artery occlusive disease. Principal symptoms
include visual loss, light-induced transient visual loss,
and ischemic ocular pain. Conjunctival and episcleral
injection, anterior chamber inflammation, and iris
neovasularization are the main anterior segment
signs. Less often, corneal edema and intumescent
cataract may develop. Posterior segment signs
include narrowed retinal arteries, dilated but not
tortuous retinal veins, dot and blot hemorrhages in
the mid-peripheral retina, microaneurysms, cotton-
wool spots, and neovascularization. Fluorescein and
ICG angiography show delayed arteriovenous transit
time and delayed/patchy choroidal filling. Clinical
and angiographic findings in combination with
various other ophthalmic ancillary tests and with
imaging of the carotid vascular system allow definitive
diagnosis. Associated systemic vascular diseases
should be investigated and treated accordingly;
surgery should be performed when appropriate. Iris
neovascularization and poor initial visual acuity are
associated with a poor visual prognosis. The mortality
rate is high (40% at 5 years).
Ocular signs and symptoms of carotid artery
occlusive disease may occur before cerebrovascular
and cardiovascular complications. As a result, oph-
thalmologists may be the first to deal with patients
suffering from carotid artery occlusive disease and
should be aware of the clinical presentation of OIS.
They should be able to recognize the established
condition, but also to suspect its presence early
enough, when subtle ocular symptoms or signs
appear. In cases where visual acuity is preserved, visual
prognosis is better when treatment is undertaken. If
diagnosis is delayed, irreversible damage may occur.
The continuing improvements in the diagnostic
techniques, in the medical management, and in the
surgical treatment of carotid artery occlusive disease
make the role of ophthalmologists increasingly
important in the early detection of the OIS. The
ophthalmologist is an important member of a multi-
disciplinary team that diagnoses and treats patients
presenting with the ocular ischemic syndrome.
MENDRINOS ET AL
XV. Method of Literature Search
Literature selection for this review was based on
a Medline database search from the period 1954 to
2008 using the following keywords as well as various
combinations of them: ocular ischemic syndrome, ocular
ischemia, carotid artery occlusion, carotid artery stenosis,
ischemic pain, amaurosis fugax, anterior segment ische-
mia, posterior segment ischemia, neovascularization,
fluorescein angiography, indocyanine green angiography,
electroretinography, visual evoked potentials, ophthalmody-
namometry, ocular plethysmography, carotid artery imag-
ing, carotid arteriography, duplex carotid ultrasound,
magnetic resonance angiography, computed tomographic
angiography, color Doppler imaging of the retrobulbal
vessels, reversed ophthalmic artery blood flow, giant cell
arteritis, Takayasu arteritis, aortic arch syndrome, carotid
endarterectomy, extracranial--intracranial bypass surgery,
carotid stenting. Additionally, relevant references
cited in these articles were also reviewed. The
literature search was not limited to the English
language; foreign language publications were also
considered. All English and French articles were
read thoroughly and for the relevant non-English,
non-French articles, their English abstracts were
reviewed. To ensure that this review is as up-to-date
as possible, Medline was regularly reviewed during
the period of preparation of the manuscript.
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The authors reported no proprietary or commercial interest in
any product mentioned or concept discussed in this article. The
authors would like to thank Prof. James-Scott Schutz, MD, for
critical revision of the manuscript.
Reprint address: Constantin J. Pournaras, MD, Department of
Ophthalmology, 22 rue Alcide Jentzer, 1211 Geneva 14, Switzer-
land. e-mail: constantin.pournaras@hcuge.ch.

Outline E. Ophthalmodynamometry
F. Ocular plethysmography
I. Introduction G. Imaging methods for the evaluation of
II. Historical review carotid occlusive disease
III. Epidemiology and pathogenesis
1. Carotid duplex ultrasound
IV. Clinical presentation
2. Color Doppler imaging of retrobulbar
A. Symptoms vessels
3. Minimally invasive methods (magnetic
1. Visual loss
resonance angiography and computed
2. Pain
tomographic angiography)
B. Ocular manifestations 4. Carotid arteriography
1. Anterior segment signs
XI. Management of ocular ischemic syndrome
2. Posterior segment signs
3. Orbital infarction syndrome A. Ocular treatment
B. Medical treatment
V. Differential diagnosis C. Surgical treatment
VI. Systemic associations
1. Carotid artery endarterectomy
VII. Giant cell arteritis
2. Carotid artery stenting
VIII. Aortic arch syndrome
3. Extracranial--intracranial arterial bypass
IX. Takayasu arteritis
surgery
X. Diagnosis and ancillary tests
A. Fluorescein angiography XII. Visual prognosis
B. Indocyanine green angiography XIII. Mortality
C. Electroretinography XIV. Summary and conclusions
D. Visual-evoked potentials XV. Method of literature search