Neurosurg Focus 36 (1):E7, 2014 ©AANS, 2014

Current endovascular treatment options for central retinal arterial occlusion: a review

Nitin Agarwal, B.S.,1 Nihar B. Gala, M.D.,1 Reza J. Karimi, M.D.,1 Roger E. Turbin, M.D.,2 Chirag D. Gandhi, M.D.,1,3 and Charles J. Prestigiacomo, M.D.1,3,4 Departments of 1Neurological Surgery, 2Ophthalmology and Visual Science, 3Radiology, and 4Neurology and Neuroscience, Rutgers New Jersey Medical School, Newark, New Jersey

Central retinal artery occlusion, although relatively rare, is an ophthalmological emergency. If left untreated, complete blindness will ensue. Conventional therapies have not significantly improved outcomes compared with the natural history of the disease. Several case series of more recent endovascular approaches, such as intraarterial fibrinolysis, report successful outcomes. Still other studies regarding intraarterial fibrinolysis do not demonstrate any significantly better outcomes, with some even indicating increased complication rates. Therefore, the authors present a review of the current endovascular treatment options for central retinal artery occlusion. (http://thejns.org/doi/abs/10.3171/2013.11.FOCUS13331)

Key Words • central retinal arterial occlusion • treatment • endovascular • fibrinolysis

entral retinal artery occlusion (CRAO) is an oph- high association of CRAO with atherosclerosis, diabetes, thalmological emergency that can result in com- and systemic hypertension.16 plete blindness in the affected eye if untreated.3,5,6, 17,29,38,41,42,45C It is a result of sudden cessation of circulation Epidemiology, Etiology, and Presentation to the inner retinal layer, which is considered to be a part of the CNS. This condition was first described in 1859 The true incidence of CRAO in the population is by Albrecht von Graefe, a famous German ophthalmolo- unknown. One report estimated CRAO to occur in 1 per gist known for his contributions in glaucoma and cataract 10,000 outpatient visits.10 The department of ophthalmol- treatment.44 Since then, there has been an abundant accu- ogy at the Western Galilee–Nahariya Medical Center in mulation of literature regarding the disease. Nahariya, Israel, estimated an incidence of acute CRAO Although the pathophysiological features of CRAO (with a less than 48-hour onset) at that institution to be ap- are well described in the literature, the natural history of proximately 0.85 per 100,000 per year or 1.13 per 10,000 this disease is poorly understood. Prolonged retinal ische- outpatient visits.38 Of these patients, 1%–2% present with mia is usually irreversible, suggesting a grim prognosis if bilateral involvement. Men are more frequently affected the occlusion is not corrected in a timely manner.38 In a than are women, and the average age at presentation is in matter of hours cellular hypoxia will ensue, with subse- the early 60s, with rare cases as early as in the 30s.1,38,40,42 quent necrosis if circulation is not restored. The central Patients suffering from central retinal artery embolism retinal artery is usually occluded by a thrombotic em- have a 56% mortality rate over 9 years, compared with bolus (of internal carotid artery or cardiac origin, 15.5% 27% for age-matched individuals without emboli.18 Life of cases); a calcified embolus (commonly of diseased car- expectancy is 5.5 years postdiagnosis for patients with diac valve origin, 10.5% of cases); or cholesterol embolus CRAO compared with 15.4 years for age-matched indi- (74.5% of cases) (Table 1).2,27,32 Other causes include sud- viduals without CRAO. den narrowing of the arterial wall (hemorrhage into an Diagnosis is usually made based on clinical history atheromatous plaque) and inflammatory processes (arte- and physical examination. Ninety percent of patients pre­ ritic CRAO) secondary to temporal arteritis.17 There is a sent with a complaint of acute, persistent, painless loss of vision. Some patients may report a history of amaurosis Abbreviations used in this paper: CRAO = central retinal artery fugax lasting anywhere from seconds to several hours. occlusion; EAGLE = European Assessment Group for Lysis in the Ophthalmoscopic examination may reveal diminished Eye; IAF = intraarterial fibrinolysis; IOP = intraocular pressure; blood vasculature in the retina, retinal edema, pale optic rt-PA = recombinant tissue plasminogen activator. disc, and a cherry red spot. Approximately 18.7% of the

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TABLE 1: Known causes of CRAO*

1. systemic hypertension 2. embolism 3. thrombotic calcified cholesterol bacterial 4. atherosclerotic changes 5. temporal arteritis 6. hypercoagulable state 7. collagen vascular disease 8. cardiac valvular disease 9. cardiac anomalies 10. oral contraceptives 11. diabetes mellitus 12. polycythemia 13. polyarteritis nodosa 14. Behçet disease Fig. 1. Fluorescein angiographic photograph of CRAO. Note the de- layed and segmented arteriolar filling (a) in each of the major arteriolar 15. syphilis trunks distal to the central occlusion, and a small segment of an inferior 16. sickle cell disease temporal arteriole (b) that is strongly enhancing and may represent a 17. migraine fragment of distal embolization from the central blockage. Venous tran- sit is severely prolonged, and the typical laminar flow is nearly absent 18. glaucoma (http://www.rvscny.com/retinalarteryocclusion.html). Copyright Retina 19. prolonged orbital pressure Vi­treous Surgeons of Central New York. Published with permission.

* According to Fraser and Siriwardena. plete; there remains some residual blood flow distal to the occlusion.12,29 This allows a window for treatment before population has some macular circulation from a cilioreti- 28 significant morbidity occurs. It has been postulated that nal artery, which is spared in CRAO. These patients will treatment is only beneficial if commenced within 8 hours show finger-like areas of normal retina with patent arteri- of occlusion.17 However, beneficial effects were seen with oles that are not connected to the occluded stalk. In 20% 18 treatment given up to 24 hours after the onset of symp- of cases, the embolus can be directly visualized. Fluores- toms.37 Furthermore, significant visual improvement was cein angiography may show delayed filling or occlusion reported with treatment given after 48 hours of ischemia.5 during the arterial phase (11–12 seconds) (Fig. 1). Nevertheless, shorter latency to treatment results in better Due to the high probability of permanent visual loss, 38 7,11,35,38 outcomes. It is therefore important to review all treat- immediate correction of the occlusion is a priority. ment options that aim to restore circulation to the ische- In less than 10% of cases, spontaneous recanalization of 38,40 mic retina. the occlusion may occur. In eyes with presenting visual Reports of spontaneous recovery are inconsistent. Cer- acuity of finger counting or worse, visual acuity deterio- 31,39 21 tain authors report no spontaneous recovery, whereas­ rated in 12% of cases. Nevertheless, medical treatment other case studies report some spontaneous recov­ery.3,25,43 should be sought out on an emergency basis. Several ther- A recent study of the natural history of CRAO concludes apeutic options exist, ranging from noninvasive medical that classification of disease is important and spontane- options to the controversial thrombolysis treatment. This ous recovery can be determined by several factors, such as review of the literature discusses all the endovascular ther- presenting symptoms and etiology of occlusion.24 apeutic options available following the onset of CRAO, with a focus on intraarterial fibrinolysis (IAF), with con- Treatment Options current recommendations. The patient may begin treatment prior to arrival in 16 Natural History the emergency room by massaging the affected eye. Me- chanical force on the central retinal artery may dislodge Central retinal artery occlusion is an ophthalmologi- the embolus and restore circulation. This technique will cal emergency that can lead to permanent visual loss if only work if the occlusion is due to an embolus. The pa- left untreated. Restoration of circulation distal to the oc- tient may also breathe expired air using a paper bag. The clusion can result in complete recovery if recanalization subsequent hypercapnia will cause vasodilation of the ret- occurs rapidly. The monkey retina can tolerate complete inal arteries, with an increase in circulation. Carbogen, a ischemia for up to 105 minutes before irreversible dam- fixed mixture of 95% oxygen and 5% carbon dioxide, may age occurs,23 and up to 4 hours in the presence of residual be used if available.13,39 Retinal arteries may also dilate af- blood circulation.22 In humans CRAO is usually not com- ter sublingual isosorbide dinitrate is administered.38 Sys-

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Unauthenticated | Downloaded 09/25/21 01:58 PM UTC Central retinal arterial occlusion treatments temic vasodilation may occur, causing decreased blood sion criteria included presence of branched retinal artery pressure. occlusion, cilioretinal artery, elevated IOP greater than 30 Immediate reduction of intraocular pressure (IOP) mm Hg, or severe general medical disease. Patients were may cause an increase in ocular perfusion pressure and randomly assigned into IAF treatment or control groups. therefore circulation as well. This may be attempted with Patients in the treatment group received a total of 50 mg intravenous or oral acetazolamide, a carbonic anhydrase rt-PA injected locally into the ophthalmic artery. Control inhibitor. 36 Mannitol may act as an osmotic diuretic and patients received conservative therapy including massage may also be used to reduce IOP. Anterior chamber para- of the eye, topical beta-blocker, acetazolamide, aspirin, centesis of aqueous humor3 and trabeculectomy19 are al- heparin, and isovolemic hemodilution. All patients were ternative methods for reducing IOP. Systemic steroids treated with heparin postprocedure for 5 days. The pri- may be used to reduce vascular endothelial edema.20 mary end point was the best corrected visual acuity as- Pentoxifylline has been shown to increase red blood cell sessed 1 month after the procedure. A recent European deformability, allowing easier passage through capillaries article states that the study was halted after the first inter- and less ischemia in CRAO.26,30 im analysis because similar outcomes were seen in both Despite the various options, a retrospective study of groups, with an increased risk of complication in the IAF 178 patients showed no significant benefit in conventional group.46 The investigators concluded that IAF cannot be conservative methods.41 Several other series suggest a low recommended in treatment of acute CRAO. Of 37 patients success rate with conservative treatment.5,14,31 The current treated with IAF, 3 (2 with transient ischemic attacks and 1 with stroke) developed periprocedural cerebrovascular thrombolytic approach, known as IAF, consists of local 1 infusion of urokinase or recombinant tissue plasminogen ischemic events. Another study reports 2 patients endur- ing complications (transient aphasia and hemiparesis) activator (rt-PA) at the site of occlusion via catheteriza- 41 tion of the ophthalmic artery. The thrombolytic agent of with IAF treatment. choice is rt-PA, due to the shorter half-life and lower risks For IAF to prove its role in the treatment of acute for complications. A meta-analysis of all previous litera- CRAO, the risk of complications must be reduced. This ture regarding IAF in cases of CRAO from 2000 suggests may be done through more optimal thrombolytic infusion marginal visual benefit compared with conventional ther- methods, use of a thrombolytic agent with shorter half- apy (Table 2).6 However, the evidence was not enough to life, or with a more experienced neurointerventionalist. recommend IAF in the treatment of CRAO. In the afore- Although discouraging, the hope for better results with mentioned retrospective study of 178 patients, 62 patients the EAGLE study lies in the improvement of the IAF pro- with CRAO were treated with IAF in which urokinase tocol. or rt-PA was used, and were compared with 116 controls Future Directions treated using conservative methods.41 Those treated with IAF had a greater chance of better outcome than those Clearly, the risk of complications of IAF in the treat- treated conservatively. Another series of 56 patients con- ment of acute CRAO must be reduced. Still, a study by cluded that IAF enhanced the chances of improvement Margo and Mack33 revealed that 39% and 37% of sur- compared with conservative treatment.1 In that study, 8 veyed adults would accept some risk of stroke and death, of 37 patients treated with IAF regained visual acuity of respectively, to triple the chances of recovering 20/100 vi- greater than 0.6 compared with none in the control group. sual acuity in one eye when binocular. Even more (80%) Although IAF seemed very promising with such would accept these risks if they were monocular. A survey abundant support in the literature, randomized controlled by Atkins et al.4 demonstrated that despite limited evi- clinical trials were needed before recommendations re- dence, a majority of US neuroophthalmologists continue garding the use of IAF in treatment of acute CRAO could to administer various conservative treatments, includ- be made. The European Assessment Group for Lysis in ing ocular massage, topical drops to reduce IOP, anterior the Eye (EAGLE) started a prospective and randomized chamber paracentesis, antiplatelet agents, and anticoagu- multicenter study in 2002 to evaluate the efficacy of IAF.15 lation. Moreover, thrombolytic agents were recommended Patients between the ages of 18 and 75 years who had acute by 23% of physicians. CRAO of less than 20 hours’ onset and presenting visual Therefore, despite potential complications, the need acuity of less than 0.32 were included in the study. Exclu- for a well-designed randomized, controlled, double-blind

TABLE 2: Studies regarding efficacy of IAF in CRAO

Authors & Year No. of Patients Thrombolytic Therapy Outcome Study Type Beatty & Au Eong, 2000 100 urokinase, streptoki- final acuity 20/20 in 14%; 10/20 in 27%; meta-analysis of 16 nase, rt-PA 1/20 or worse in 60.6% studies Schmidt et al., 2002 178 urokinase, rt-PA partial or greater improvement seen in case series 58% treated w/ IAF compared to 29% treated conservatively Arnold et al., 2005 56 urokinase final acuity 12/20 or greater in 22% case series treated w/ IAF compared to 0% treated conservatively

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Unauthenticated | Downloaded 09/25/21 01:58 PM UTC N. Agarwal et al. clinical trial evaluating the effect of thrombolysis in tral retinal artery occlusion. Ophthalmology 102:2029–2035, CRAO continues to be considered. However, as echoed by 1995 Biousse,8 the first step toward a multicenter trial may be 4. Atkins EJ, Bruce BB, Newman NJ, Biousse V: Translation of clinical studies to clinical practice: survey on the treatment of forming a consensus on treatment protocols. Evaluations central retinal artery occlusion. Am J Ophthalmol 148:172– of patients with acute CRAO before and after intervention 173, 2009 must be conducted, with organization of pilot data into 5. Augsburger JJ, Magargal LE: Visual prognosis following treat- an international registry. Meanwhile, alternative thera- ment of acute central retinal artery obstruction. Br J Ophthal- peutic strategies for CRAO should also be considered. To mol 64:913–917, 1980 this end, given the efficacy of intravenous rt-Pa for fibrin- 6. Beatty S, Au Eong KG: Local intra-arterial fibrinolysis for platelet clot lysis in ischemic stroke and myocardial in- acute occlusion of the central retinal artery: a meta-analysis of farction, the role of systemic rt-Pa has also been explored the published data. Br J Ophthalmol 84:914–916, 2000 34 7. Beiran I, Reissman P, Scharf J, Nahum Z, Miller B: Hyperbaric for CRAO. In a systematic review of 103 cases of acute oxygenation combined with nifedipine treatment for recent- 9 CRAO, Biousse et al. reported a 48.5% improvement of onset retinal artery occlusion. Eur J Ophthalmol 3:89–94, at least 3 lines of visual acuity. Ultimately, given that the 1993 treatment window probably does not exceed 6–12 hours, 8. Biousse V: Thrombolysis for acute central retinal artery occlu- developing quick transportation modalities for patients to sion: is it time? Am J Ophthalmol 146:631–634, 2008 emergency departments is essential. For now, heightened 9. Biousse V, Calvetti O, Bruce BB, Newman NJ: Thrombolysis for central retinal artery occlusion. J Neuroophthalmol 27: patient awareness and physician collaboration with emer- 215–230, 2007 gency rooms, stroke units, and interventionists is encour- 10. Brown GC: Retinal arterial obstructive disease, in Schachat aged. AP, Murphy RB, Patz A (eds): Medical Retina. Retina, Vol 2. St. Louis: CV Mosby, 1989, pp 1361–1377 Conclusions 11. Chen JC, Cheema D: Repeated anterior chamber paracentesis for the treatment of central retinal artery occlusion. Can J There is an abundance of literature regarding treat- Ophthalmol 29:207–209, 1994 ment options for CRAO. Conservative therapy has been 12. David NJ, Norton EW, Gass JD, Beauchamp J: Fluorescein an- used for decades with variable success, but it has not been giography in central retinal artery occlusion. Arch Ophthal- mol 77:619–629, 1967 shown to improve outcomes significantly compared with 13. Deutsch TA, Read JS, Ernest JT, Goldstick TK: Effects of oxy- no treatment. A recent endovascular approach involved gen and carbon dioxide on the retinal vasculature in humans. IAF with urokinase or rt-PA. Several series report suc- Arch Ophthalmol 101:1278–1280, 1983 cessful outcomes in patients treated with IAF; however, 14. Duker JS, Sivalingam A, Brown GC, Reber R: A prospective a recent prospective randomized controlled multicenter study of acute central retinal artery obstruction. The incidence clinical study has not yet shown significantly better out- of secondary ocular neovascularization. Arch Ophthalmol comes. Attention must be given to reduction and/or better 109:339–342, 1991 management of complications associated with IAF as well 15. Feltgen N, Neubauer A, Jurklies B, Schmoor C, Schmidt D, Wanke J, et al: Multicenter study of the European Assessment as more optimal infusion methods. Given the current evi- Group for Lysis in the Eye (EAGLE) for the treatment of cen- dence, IAF cannot yet be recommended for the treatment tral retinal artery occlusion: design issues and implications. of acute CRAO. EAGLE Study report no. 1: EAGLE Study report no. 1. Grae- fes Arch Clin Exp Ophthalmol 244:950–956, 2006 Disclosure 16. Ffytche TJ: A rationalization of treatment of central retinal ar­ The authors report no conflict of interest concerning the mate- tery occlusion. Trans Ophthalmol Soc U K 94:468–479, 1974 rials or methods used in this study or the findings specified in this 17. Fraser S, Siriwardena D: Interventions for acute non-arteritic paper. central retinal artery occlusion. Cochrane Database Syst Rev Author contributions to the study and manuscript prepara- (1):CD001989, 2002 tion include the following. Conception and design: Prestigiacomo, 18. Graham RH, Ebrahim SA: Central retinal artery occlusion. Agarwal, Gala. Acquisition of data: Agarwal, Gala. Analysis and Medscape. (http://emedicine.medscape.com/article/1223625- interpretation of data: Agarwal, Gala. Drafting the article: Agarwal, overview) [Accessed November 20, 2013] Gala. Critically revising the article: Agarwal, Gala, Karimi, Turbin, 19. Harvey PA, Winder S, Talbot JF: Trabeculectomy for central Gandhi. Reviewed submitted version of manuscript: all authors. retinal artery occlusion. Eye (Lond) 14:256–257, 2000 Approved the final version of the manuscript on behalf of all authors: 20. Hausmann N, Richard G: Effect of high dose steroid bolus on BMJ Prestigiacomo.­ Statistical analysis: Agarwal. Administrative/tech­ occlusion of ocular central artery: angiographic study. 303:1445–1446, 1991 nical/material support: Prestigiacomo, Gandhi. Study supervision: 21. Hayreh SS: Acute retinal arterial occlusive disorders. Prog Re- Pres­tigiacomo. tin Eye Res 30:359–394, 2011 References 22. Hayreh SS: Retinal arterial occlusion with LIF using rTPA. Ophthalmology 106:1236–1239, 1999 1. Arnold M, Koerner U, Remonda L, Nedeltchev K, Mattle HP, 23. Hayreh SS, Kolder HE, Weingeist TA: Central retinal artery Schroth G, et al: Comparison of intra-arterial thrombolysis occlusion and retinal tolerance time. Ophthalmology 87:75– with conventional treatment in patients with acute central reti- 78, 1980 nal artery occlusion. J Neurol Neurosurg Psychiatry 76:196– 24. Hayreh SS, Zimmerman MB: Central retinal artery occlusion: 199, 2005 visual outcome. Am J Ophthalmol 140:376–391, 2005 2. Arruga J, Sanders MD: Ophthalmologic findings in 70 patients 25. Humphrey WT: Central retinal artery spasm. Ann Ophthal- with evidence of retinal embolism. Ophthalmology 89:1336– mol 11:877–881, 1979 1347, 1982 26. Iwafune Y, Yoshimoto H: Clinical use of pentoxifylline in 3. Atebara NH, Brown GC, Cater J: Efficacy of anterior chamber haemorrhagic disorders of the retina. 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27. Jenkins HS, Marcus DF: Central retinal artery occlusion. JA- CO2 on ocular fundus pulsations. Exp Eye Res 63:351–355, CEP 8:363–367, 1979 1996 28. Justice J Jr, Lehmann RP: Cilioretinal arteries. A study based 40. Schmidt D, Schumacher M, Wakhloo AK: Microcatheter uro- on review of stereo fundus photographs and fluorescein angio- kinase infusion in central retinal artery occlusion. Am J Oph- graphic findings. Arch Ophthalmol 94:1355–1358, 1976 thalmol 113:429–434, 1992 29. Karjalainen K: Occlusion of the central retinal artery and reti- 41. Schmidt DP, Schulte-Mönting J, Schumacher M: Prognosis of nal branch arterioles. A clinical, tonographic and fluorescein central retinal artery occlusion: local intraarterial fibrinolysis angiographic study of 175 patients. Acta Ophthalmol Suppl versus conservative treatment. AJNR Am J Neuroradiol 23: 109:1–95, 1971 1301–1307, 2002 30. Kieswetter H, Körber N, Jung F, Reim M: Rheologic findings 42. Schumacher M, Schmidt D, Wakhloo AK: Intra-arterial fibri- in patients with acute central retinal artery occlusion. Graefes nolytic therapy in central retinal artery occlusion. Neuroradi- Arch Clin Exp Ophthalmol 220:92–95, 1983 ology 35:600–605, 1993 31. Lorentzen SE: Occlusion of the central retinal artery. A follow- 43. Shimizu K, Numaga J, Takahashi M, Matsunaga T: [A case of up. Acta Ophthalmol (Copenh) 47:690–703, 1969 Sneddon syndrome.] Nippon Ganka Gakkai Zasshi 99:104– 32. Mangat HS: Retinal artery occlusion. Surv Ophthalmol 40: 108, 1995 (Jpn) 145–156, 1995 44. Von Graefe A: Über Embolie der Arteria centralis retinae als 33. Margo CE, Mack WP: Therapeutic decisions involving dispa- Ursache plötzlicher Erblindung. Graefes Arch Ophthalmol rate clinical outcomes: patient preference survey for treatment 5:136–185, 1859 of central retinal artery occlusion. Ophthalmology 103:691– 45. Weber J, Remonda L, Mattle HP, Koerner U, Baumgartner RW, 696, 1996 34. National Institute of Neurological Disorders and Stroke rt-PA Sturzenegger M, et al: Selective intra-arterial fibrinolysis of Stroke Study Group: Tissue plasminogen activator for acute acute central retinal artery occlusion. Stroke 29:2076–2079, ischemic stroke. N Engl J Med 333:1581–1587, 1995 1998 35. Perkins SA, Magargal LE, Augsburger JJ, Sanborn GE: The 46. Wolf A, Schumacher M, Neubauer AS, Schmoor C, Gall C, idling retina: reversible visual loss in central retinal artery ob- Jurklies B, et al: [Comparison of superselective intraarterial fi- struction. Ann Ophthalmol 19:3–6, 1987 brinolysis with conservative therapy. Use in patients with acute 36. Rassam SM, Patel V, Kohner EM: The effect of acetazolamide non-arteritic central retinal artery occlusion.] Ophthalmologe on the retinal circulation. Eye (Lond) 7:697–702, 1993 107:799–805, 2010 (Ger) 37. Richard G, Lerche RC, Knospe V, Zeumer H: Treatment of retinal arterial occlusion with local fibrinolysis using recombi- nant tissue plasminogen activator. Ophthalmology 106:768– Manuscript submitted August 11, 2013. 773, 1999 Accepted November 6, 2013. 38. Rumelt S, Dorenboim Y, Rehany U: Aggressive systematic Please include this information when citing this paper: DOI: treatment for central retinal artery occlusion. Am J Ophthal- 10.3171/2013.11.FOCUS13331. mol 128:733–738, 1999 Address correspondence to: Charles J. Prestigiacomo, M.D., 90 39. Schmetterer L, Lexer F, Findl O, Graselli U, Eichler HG, Wolzt Bergen St., Ste. 8100, P.O. Box 1709, Newark, NJ 07101-1709. M: The effect of inhalation of different mixtures of O2 and email: [email protected].

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