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

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

COURTESY: NATURE PUBLISHING COMPANY

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

COURTESY: NATURE PUBLISHING COMPANY

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 4 and 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

COURTESY: NATURE PUBLISHING COMPANY

COURTESY: NATURE PUBLISHING COMPANY

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

COURTESY: NATURE PUBLISHING COMPANY

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

COURTESY: ELSEVIER

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

COURTESY: NATURE PUBLISHING COMPANY

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.^14,21,22 A 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

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.¹ Doctors 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 post-CRAO, 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 life-threatening complications. ⁴

One final and much debated complication is the prevalence and etiology of ocular neovascularization following CRAO. For example, Hayreh et al²⁰ showed no cause-effect relationship between CRAO and ocular neovascularization,²⁰ but, in contrast, Rudkin et al³⁷ showed 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 al³⁷ showed 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 in Figure 6.⁴

Figure 6. Fundus photograph of the left eye showing neovascularization of the optic disc after CRAO.⁴

COURTESY: NATURE PUBLISHING COMPANY

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

1. Cugati S, Varma DD, Chen CS, Lee AW. Treatment options for central retinal artery occlusion. Curr Treat Options Neurol. 2013;15:63-77.
2. Rumelt S, Dorenboim Y, Rehany U. Aggressive systematic treatment for central retinal artery occlusion. Am J Ophthalmol. 1999;128:733-738.
3. Hayreh SS, Zimmerman MB. Central retinal artery occlusion: visual outcome. Am J Ophthalmol. 2005;140:376-391.
4. Varma DD, Cugati S, Lee AW, Chen CS. A review of central retinal artery occlusion: clinical presentation and management. Eye. 2013;27:699-697.
5. Singh S, Dass R. The central artery of the retina. I. Origin and course. Br J Ophthalmol. 1960;44:193-212.
6. Hayreh SS. Acute retinal arterial occlusive disorders. Prog Retin Eye Res. 2011;30:359-394.
7. Justice Jr J, Lehmann RP. Cilioretinal arteries: a study based on review of stereo fundus photographs and fluorescein angiographic findings. Arch Ophthalmol. 1976;94:1355-1358.
8. Hayreh S. Pathogenesis of occlusion of the central retinal vessels. Am J Ophthalmol. 1971;72:998-1011.
9. Hayreh SS. Anatomy and physiology of the optic nervehead. Trans Am Acad Ophthalmol Otolaryngol. 1974;78:OP240-OP254.
10. Arruga J, Sanders M. Ophthalmologic findings in 70 patients with evidence of retinal embolism. Ophthalmology. 1982;89:1336-1347.
11. Duker J. Retinal Arterial Obstruction Ophthalmology. St Louis, MO; Mosby; 2004:854-861.
12. Mangat HS. Retinal artery occlusion. Surv Ophthalmol. 1995;40:145-156.
13. Hayreh SS, Zimmerman MB, Kimura A, Sanon A. Central retinal artery occlusion. Retinal survival time. Exp Eye Res. 2004;78:723-736.
14. Chen CS, Lee AW. Management of acute central retinal artery occlusion. Nat Clin Pract Neurol. 2008;4:376-383.
15. Rudkin A, Lee A, Chen C. Vascular risk factors for central retinal artery occlusion. Eye. 2009;24:678-681.
16. Schmidt DP, Schulte-Mönting J, Schumacher M. Prognosis of central retinal artery occlusion: local intraarterial fibrinolysis versus conservative treatment. Am J Neuroradiol. 2002;23:1301-1307.
17. Kline L. The natural history of patients with amaurosis fugax. Ophthalmol Clin N Am. 1996;9:351-358.
18. Hayreh SS, Zimmerman MB. Fundus changes in central retinal artery occlusion. Retina. 2007;27:276-289.
19. Shinoda K, Yamada K, Matsumoto CS, Kimoto K, Nakatsuka K. Changes in retinal thickness are correlated with alterations of electroretinogram in eyes with central retinal artery occlusion. Graefes Arch Clin Exp Ophthalmol. 2008;246:949-954.
20. Hayreh SS, Podhajsky PA, Zimmerman MB. Retinal artery occlusion: associated systemic and ophthalmic abnormalities. Ophthalmology. 2009;116:1928-1936.
21. Brown G, Magargal L, Shields J, Goldberg R, Walsh P. Retinal arterial obstruction in children and young adults. Ophthalmology 1981;88:18-25.
22. Greven CM, Slusher MM, Weaver RG. Retinal arterial occlusions in young adults. Am J Ophthalmol. 1995;120:776-783.
23. Brown G, Magargal L, Augsburger J, Shields J. Preretinal arterial loops and retinal arterial occlusion. Am J Ophthalmol. 1979;87:646-651.
24. Atebara NH, Brown GC, Cater J. Efficacy of anterior chamber paracentesis and Carbogen in treating acute nonarteritic central retinal artery occlusion. Ophthalmology. 1995;102:2029-2034; discussion, 2034-2035.
25. Biousse V, Calvetti O, Bruce BB, Newman NJ. Thrombolysis for central retinal artery occlusion. J Neuro-ophthalmol. 2007;27:215-230.
26. Karjalainen K. Occlusion of the central retinal artery and retinal branch arterioles. A clinical, tonographic and fluorescein angiographic study of 175 patients. Acta Ophthalmol. 1971;109(Suppl):1-95.
27. Mueller AJ, Neubauer AS, Schaller U, Kampik A. Evaluation of minimally invasive therapies and rationale for a prospective randomized trial to evaluate selective intra-arterial lysis for clinically complete central retinal artery occlusion. Arch Ophthalmol. 2003;121:1377-1381.
28. Margo CE, Mack WP. Therapeutic decisions involving disparate clinical outcomes: patient preference survey for treatment of central retinal artery occlusion. Ophthalmology. 1996;103:691-696.
29. Fraser SG, Adams W. Interventions for acute nonarteritic central retinal artery occlusion. Cochrane Database Syst Rev 2009;1:CD001989.
30. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke. 2006;37:922-928.
31. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA. 1995;274:1017-1025.
32. Arnold M, Koerner U, Remonda L, et al. Comparison of intra-arterial thrombolysis with conventional treatment in patients with acute central retinal artery occlusion. J Neurol Neurosurg Psychiatry. 2005;76:196-199.
33. Aldrich EM, Lee AW, Chen CS, et al. Local intraarterial fibrinolysis administered in aliquots for the treatment of central retinal artery occlusion. Stroke. 2008;39:1746-1750.
34. Hattenbach LO, Kuhli-Hattenbach C, Scharrer I, Baatz H. Intravenous thrombolysis with low-dose recombinant tissue plasminogen activator in central retinal artery occlusion. Am J Ophthalmol. 2008;146:700-706.e701.
35. Chen CS, Lee AW, Campbell B, et al. Efficacy of intravenous tissue-type plasminogen activator in central retinal artery occlusion. Stroke. 2011;42:2229-2234.
36. Schumacher M, Schmidt D, Jurklies B, et al. Central retinal artery occlusion: local intra-arterial fibrinolysis versus conservative treatment, a multicenter randomized trial. Ophthalmology. 2010;117:1367-1375.e1361.
37. Rudkin AK, Lee AW, Chen CS. Ocular neovascularization following central retinal artery occlusion: prevalence and timing of onset. Eur J Ophthalmol. 2010;20:1042-1046.
38. Schmidt D, Hetzel A, Geibel-Zehender A, Schulte-Monting J. Systemic diseases in non-inflammatory branch and central retinal artery occlusion-an overview of 416 patients. Eur J Med Res. 2007;12:595-603.