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Central Retinal Artery Occlusion: General Overview, Diagnosis, and Treatment

Causing sudden vision loss, this rare but troubling condition is linked to cardiovascular disease.
DANIEL D. VARMA, MBBS, BBiomedSc ANDREW W. LEE, MBBS, MPH, FRACP CELIA
S. CHEN, MBBS, PhD, FRANZCO

Daniel D. Varma, MBBS, BBiomedSc, and Andrew W. Lee, MBBS, MPH, FRACP, are on the
faculty of the Flinders Comprehensive Stroke Centre of Flinders Medical Centre and University in
Bedford Park, South Australia. Celia S. Chen, MBBS, PhD, FRANZCO, is on the faculty of the
Flinders Neuro-ophthalmology Unit. None of the authors reports any financial interests in any of the
products mentioned in this article. Dr. Varma can be reached via e-mail at
danieldhirenvarma@gmail.com.

Central retinal artery occlusion (CRAO), or a stroke of the eye, is an ocular emergency. It represents
end-organ ischemia and is analogous to terminal branch occlusion in cerebral stroke. 1
The incidence of CRAO is 1:100,000, with more than 75% of sufferers having a visual acuity of
20/400 or worse in the affected eye, causing significant functional morbidity. 2,3 CRAO usually occurs
on a background of atherosclerotic disease, with patients at future risk for cerebral stroke and
ischemic heart disease, as they share the same risk factors. 4
Accurate, prompt diagnosis of CRAO is crucial for acute management and to prevent future ischemic
events. CRAO requires a comprehensive diagnostic work-up, focusing on the evaluation of
atherosclerotic disease and risk factors.
No guideline-endorsed evidence exists for the treatment of CRAO. Current treatment options include
standard therapies and thrombolytics.
ANATOMY AND PHYSIOLOGY OF CRAO
The central retinal artery (CRA) is a branch of the ophthalmic artery, which is the first branch of the
internal carotid artery.5 The CRA supplies blood to the surface layer of the optic disc.

Figure 1. Fundus photographs showing types of retinal emboli: A) cholesterol embolus; B) fibrin
embolus; C) calcific embolus.4
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The arterial tree of the CRA then further divides ultimately to supply the four quadrants of the
retina.6 CRAO starves the retina of blood, causing a decrease in inner retinal layer thickness.
CRAO has an important anatomical variant, a cilio-retinal artery, found in up to 49.5% of
patients.7 This artery supplies the maculopapular bundle, which contains the maximum amount of
photoreceptors required for central vision. The presence of a cilioretinal artery indicates the

possibility of maintaining inner retinal fiber layer thickness and central vision in the event of a
CRAO.3
However, a detailed study of 260 eyes, 35 with this artery, showed that 60% had poor visual acuity, of
6/30 or worse.3 Such poor results emphasize the importance of the size of the cilioretinal artery and
the area it supplies.
Locations of CRAO
Conjecture surrounds where CRAO most commonly occurs. The most common cause is an embolus
that lodges in the narrowest part of the CRA lumen. Such emboli occur where the CRA pierces the
dural sheath of the optic nerve. 6,8,9 The major source of emboli is carotid artery disease secondary to
atherosclerotic plaques. Carotid stenosis and the heart are also notable sources. 6 In 74% of patients,
emboli consist of cholesterol, with the remainder composed of calcific material or fibrin (Figure
1).4,10 Thrombi occurring immediately posterior to the lamina cibrosa are another probable cause
(Figure 2).11,12
RETINAL TOLERANCE TIME IN CRAO
Occlusion of the CRA causes potentially irreversible retinal damage. To save the retina and vision in
that eye, the physician must remove the offending embolus/thrombus.
The best studies measuring retinal ischemic tolerance time have been based on electrophysiological,
histopathological, and morphometric studies in old, hypertensive, atherosclerotic rhesus monkeys. 13
An exact retinal tolerance time is unknown, but based on this animal model, it appears to be no longer
than 240 minutes. This study also showed that treatment within 97 minutes provided the greatest
chance for complete visual recovery.13

Figure 2. Color fundus photograph of the right eye showing acute nonarteritic CRAO with
cherry red spot and cattle trucking of the arterioles. 4
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Types of CRAO
Four different types of CRAO3 exist:

nonarteritic permanent CRAO;

nonarteritic transient CRAO;

nonarteritic CRAO with cilioretinal sparing; and

arteritic CRAO.

Nonarteritic permanent CRAO accounts for more than 66% of CRAO cases. 14-16 Nonarteritic transient
CRAO is a transient ischemic event of the eye, which occurs in 15% of CRAO cases and confers a
1% per year risk that a patient will suffer a future permanent CRAO. 17
The third type of CRAO is nonarteritic CRAO with cilioretinal sparing (Figure 3).4 Arteritic CRAO
occurs in 4.5% of CRAO patients and results in giant cell arteritis (Figure 4).1,3
DIAGNOSTICS OF CRAO
Acute Presentation and Ocular Findings
A CRAO diagnosis is based on recognizing its clinical features from the patient history and ocular
examination. CRAO presents as sudden nonpainful visual loss in one eye, with a Snellen VA of
counting fingers or worse in 74% of patients.3
Ocular findings are based upon fundoscopy, fluorescein angiography, and OCT. These findings are
based on time from CRAO and on the type of CRAO.4
Ocular findings by time can be seen in Tables 1 and 2.18 Some of these findings appear in Figures
2 and 3.4 Fundoscopy photographs and FA time-lapse photographs demonstrating delayed arterial
filling with reduced arterial caliber due to acute CRAO appear in Figure 4and 5.1,4 Findings from
OCT may show increased inner retinal layer thickness in the acute stage of CRAO, due to retinal
edema and optic nerve swelling.19
Table 1. Early Findings Occuring Within Seven Days of CRAO
Ocular Findings

Occurrence (%)

Retinal opacity at posterior pole

90

Cherry red-spot

90

Optic disc pallor

39

Retinal arterial attenuation

32

Optic disk edema

22

Cattle trucking

19

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Table 2. Later Findings Based on Survivorship Curves
Ocular Findings

Occurrence (%)

Optic atrophy

91

Retinal arterial attenuation

58

Cilioretinal collaterals

18

Macular retinal pigment epithelial changes

11

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Figure 3. Color fundus photograph of the right eye, showing CRAO with cilioretinal artery
sparing with orange perfused retina in the distribution of the cilioretinal artery. The rest of the
retina is pale and infarcted.4
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Figure 4. Color fundus photograph of the left eye showing arteritic central retinal artery
occlusion (top left), followed by serial fundus fluorescein angiography (FFA) photos showing
delayed arterial filling and choroidal ischSemia.1
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Figure 5. FFA of the right eye showing delays in the arterial filling in CRAO at 32 s (top left), 1
m 40 s (top right), 3 m 44 s (bottom left), and 5 m 35 s (bottom right). 4
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The Importance of Risk Factor Evaluation
Central retinal artery occlusion, especially if it is a sentinel event, is usually the result of a serious
underlying pathology likely atherosclerosis. A recent single-center, randomized audit found that
64% of patients suffering from CRAO had at least one undiagnosed vascular risk factor, with
hyperlipidemia, hypertension, and diabetes the most common. 15
To this end, a comprehensive evaluation of risk factors, from the medical history, physical
examination, and investigations are crucial for preventing future acute ischemic events and for
diagnosing and optimally treating chronic conditions.
Medical and Family Histories

Evaluation of risk factors begins with a thorough history with a vascular focus. The physician must
ask the patient about a history of hypertension, valvular heart disease, ischemic heart disease, diabetes
mellitus, carotid artery disease, coronary artery disease, transient ischemic attacks, past stroke,
smoking, and renal disease.4,20
If the patient is younger than 50 years, the doctor should consider diferent proatherogenic states,
including hyperhomocystenemia, factor V Leiden, protein C and S, antithrombin deficiencies,
antiphospholipid syndrome, prothrombin gene mutations, sickle cell disease, vasculitis, oral
contraceptive use, intravenous drug use, migraine due to vasospasm, and paraneoplastic
syndromes.14,21,22A thorough family history for these risk factors is also essential.
Physician Examination
The physical examination required to evaluate vascular risk in a CRAO consists of ocular and
systemic findings. The ocular examination should focus on potential ocular risk factors, such as raised
IOP, optic nerve head drusen, and preretinal arterial loops. These conditions decrease perfusion
pressure of the optic nerve head.21,23
Patients older than 50 years with CRAO and a waxy pale optic disc require a work-up to exclude
temporal arteritis.4 The physician should also check the contralateral eye for clues to possible CRAO
etiology. Signs of hypertensive retinopathy, arteriole changes, or previous vaso-occlusive disease may
also be present.
Systemic findings suggesting vascular risk and requiring evaluation include radial pulse rate and
rhythm, irregular rhythms, such as atrial fibrillation that predispose to emboli, and blood pressure
measurement due to the relationship between CRAO and hypertension.
In patients older than 50 years, the physician should examine the scalp for tenderness and the nodular
temporal arteries to eliminate the possibility of temporal arteritis. In younger patients, a targeted
examination is appropriate, looking for signs suggestive of an autoimmune connective tissue disease,
which could predispose to vasculitis.4
Ancillary investigations are also important diagnostically and can be based on specific features of the
patient's demographics, history, and physical examination (Table 3).4
Table 3. Suggested Vascular Workup for Patients With CRAO
Common vascular risk factors (all
Blood pressure
patients)

Fasting lipids and lipid profile

Fasting blood sugar

Exclusion of arteritic CRAO


ESR, CRP, Platelet count
Investigations for embolic sources

Duplex carotid ultrasound

Echocardiogram

Thrombophilia screen (protein C and S, factor V Leiden,


Younger patients (<50 years old)
antiphospholipid antibody), vasculitic screen (ANA, ENA,
with no vascular risk factors
ANCA, ACE)

Treatment Options for CRAO


The natural history of CRAO suggests spontaneous reperfusion and visual recovery (at least a 3-line
improvement in Snellen VA) are possible, but they occur in only approximately 10% of people. 24
As a result, definitive and effective treatment for CRAO is necessary. Unfortunately such treatment
has been difficult to achieve because people seldom present acutely, and CRAO is a time-critical
pathology.
As such, no consensus exists for treatment or guideline-based therapy. 25 The two main types of
treatment are so-called standard treatments and intravenous and intra-arterial alteplase (tPA; Activase,
Genentech, South San Francisco, CA).
Standard Treatments
Much of the data for standard treatments for CRAO have been observational. None of the therapies,
whether used as monotherapy or in combination, has altered outcomes more than the natural history
of the disease.24,26-28
Results of two randomized, controlled trials that investigated conservative treatments suggested oral
pentoxifylline (Trental, Sanofi, Bridgewater, NJ) and enhanced external counterpulsation could play
roles in the treatment of CRAO. Although increased retinal perfusion resulted, it did not convert into
an improvement in VA.29
A summary of the standard therapies available (used alone and in combination) and their mechanisms
of action appears in Table 4.1,4
Thrombolytic Treatments
Thrombolysis with tPA, a naturally occurring fibrinolytic agent found on vascular endothelial cells
causing clot lysis, has shown promise. 1Doctors can give tPA via IA or IV administration, but they
should assess the positives and negatives for the route of administration.

Intravenous tPA has the advantages of easier access and shorter procedural time, and it can form a part
of a standard ischemic stroke protocol. It does not require a neurointerventionalist, and it has a
decreased risk of direct vascular injury and hemorrhagic complications. 30-32
Intra-arterial thrombolysis has demonstrated efficacy in small, retrospective studies and in several
open-label observational trials, the latter showing IA tPA was effective in CRAO, causing an
improvement in VA in 60% to 70% of patients.4
A Johns Hopkins Hospital study of 42 CRAO patients and an interventional case series supported
these results. In these two trials, investigators administered IA tPA at 15 hours and 6.5 hours postCRAO, respectively. Both studies showed statistically significant improvement in VA of 3 lines or
more, compared with control patients.33,34
Time Is Tissue
With CRAO, time is tissue, with the retinal ischemic tolerance time appearing to be between four
and 6.5 hours before irreversible damage occurs. 13,34,35 Support for this urgency came from a study in
which doctors gave IV tPA up to 24 hours post-CRAO. They noted no significant changes in VA.
However, when the authors divided the study patients into subgroups by time to intervention, a
significant improvement of VA more than 3 lines emerged in the patients who received tPA within 6
hours of onset.35
To add weight to this finding, a prospective, multicenter, randomized, controlled trial, undertaken by
the European Assessment Group for Lysis in the EYE (EAGLE), compared outcomes for IA tPA vs
conservative standard treatment (CST). They found no statistically significant differences in clinical
improvement.
However, the patients in this trial received tPA at up to 20 hours. As a result, many patients likely fell
outside the cutoff time for retinal ischemia tolerance, correlating with the poor results. 36
Possible Risks
Thrombolytic agents also have risks. In the EAGLE study, adverse events occurred in 37% of patients
who received a thrombolytic, compared with 4.3% in the CST group. 36 Future studies should carefully
weigh the decision to give tPA based on the potential for restoration of sight vs that for lifethreatening complications. 4
One final and much debated complication is the prevalence and etiology of ocular neovascularization
following CRAO. For example, Hayreh et al 20 showed no cause-effect relationship between CRAO
and ocular neovascularization,20 but, in contrast, Rudkin et al37showed a temporal relationship
between CRAO and neovascularization events. 38
Due to contrasting opinions, no consensus exists on the followup regimen to assess for this
complication. However, Rudkin et al 37showed neovascularization to occur at approximately eight
weeks, with a range between two and 16 weeks, so monitoring at two-week intervals from CRAO
occurrence up to four months post-CRAO would appear prudent. 37 An example of neovascularization
can be seen inFigure 6.4

Figure 6. Fundus photograph of the left eye showing neovascularization of the optic disc after
CRAO.4
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CONCLUSION
Long-term prevention of CRAO and other ischemic events, requires ongoing evaluation and
management of all systemic atherosclerotic risk factors. Effective primary and secondary prevention
measures begin with a balanced diet and regular exercise, and they flow down to optimizing medical
management of chronic vascular conditions.38
Central retinal artery occlusion critically threatens the retina. An effective guideline-based treatment is
necessary, with IV and IA thrombolytic agents appearing to offer the best hope. Larger future studies
are necessary to better establish the efficacy of these agents, with particular focus on giving tPA
within six hours of symptom onset. Such administration depends on a rapid, accurate diagnosis of
CRAO.
Primary and secondary prevention, comprehensive evaluation, and management of all vascular risk
factors are potentially even more important, because such measures can prevent CRAO, and other
ischemic phenomena as well. RP
REFERENCES