Visual Recovery in 2 Cases of Central Retinal Artery Occlusion Treated With Prompt Intra-ophthalmic Artery Fibrinolysis

Background: Central retinal artery occlusion (CRAO) rapidly produces inner retinal ischemia and irreversible vision loss. Although many therapeutic interventions have been proposed, no interventions have proven effective in restoring vision in large randomized controlled trials and final visual outcome in most patients is very poor. Methods: Retrospective case series. Results: We describe 2 cases of CRAO occurring after uncomplicated cataract surgery under topical anesthesia and rapidly diagnosed. Both had very severe vision loss at presentation with dramatic improvement after intra-ophthalmic artery fibrinolysis administered 2.75 and 5.5 hours after symptom onset. Conclusions: Sudden monocular vision loss is an ophthalmologic emergency as CRAO must be ruled out and if diagnosed, rapid intervention should be performed. Devastating vision loss can be prevented if interventional neuroradiology is trained and available on a 24-hour basis for administration of local intra-arterial thrombolysis.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Visual Recovery in 2 Cases of Central Retinal Artery Occlusion Treated With Prompt Intra-ophthalmic Artery Fibrinolysis Laura Donaldson, MD, PhD, Patrick Nicholson, MD, Edward Margolin, MD, FRCSC Background: Central retinal artery occlusion (CRAO) rapidly produces inner retinal ischemia and irreversible vision loss. Although many therapeutic interventions have been proposed, no interventions have proven effective in restoring vision in large randomized controlled trials and final visual outcome in most patients is very poor. Methods: Retrospective case series. Results: We describe 2 cases of CRAO occurring after uncomplicated cataract surgery under topical anesthesia and rapidly diagnosed. Both had very severe vision loss at presentation with dramatic improvement after intraophthalmic artery fibrinolysis administered 2.75 and 5.5 hours after symptom onset. Conclusions: Sudden monocular vision loss is an ophthalmologic emergency as CRAO must be ruled out and if diagnosed, rapid intervention should be performed. Devastating vision loss can be prevented if interventional neuroradiology is trained and available on a 24-hour basis for administration of local intra-arterial thrombolysis. Journal of Neuro-Ophthalmology 2023;43:383–386 doi: 10.1097/WNO.0000000000001785 © 2023 by North American Neuro-Ophthalmology Society composed of calcified material or platelet-fibrin clumps (2). Only a small percentage of cases of CRAO are vasculitisrelated (3); thus, most patients could potentially be treated with fibrinolytic agents once this has been ruled out. Neural tissue of the retina has very limited tolerance for ischemia, with animal studies suggesting a window of less than 240 minutes of hypoxia for any prospect of vision recovery (4) and if CRAO is complete (with 100% blockage of the artery), irreversible damage and neuronal cell death likely occurs much sooner (5). Although embolic cerebral infarctions can be treated with thrombolysis within 4.5–6 hours of symptom onset or mechanical thrombectomy up to 24 hours after symptoms (6), there is no evidence-based intervention currently recommended for treatment of CRAO. One important reason for this is the difficulty of rapidly diagnosing this condition. Ophthalmoscopy or fundus photography is required to distinguish CRAO from other causes of sudden vision loss and is often not available in an emergency department setting. METHODS AND RESULTS C entral retinal artery occlusion (CRAO) is a rare cause of vision loss that in most cases is severe and irreversible (1). Most cases are embolic in nature, usually secondary to atherosclerosis within the ipsilateral carotid tree or less commonly emboli are cardiac in origin. Cholesterol is the most common plaque material, with a small proportion of emboli Division of Ophthalmology (LD), Department of Surgery, McMaster University, Hamilton, Canada; and Department of Medical Imaging (PN), University Health Network, Department of Ophthalmology and Vision Sciences (EM), Faculty of Medicine, Division of Neurology (EM), Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Canada. The authors report no conflicts of interest. Address correspondence to Edward Margolin, MD, FRCSC, Dipl. ABO, Division of Neurology, Department of Medicine, 801 Eglinton Avenue West, Suite 301, Toronto, ON M5N 1E3, Canada; E-mail: [e-mail] Donaldson et al: J Neuro-Ophthalmol 2023; 43: 383-386 We describe 2 cases of CRAO occurring in the perioperative period of uncomplicated cataract surgery under topical anesthesia, which were rapidly diagnosed and treated with local intra-arterial thrombolysis (LIT) at 2.75 and 5.5 hours after symptom onset, both with excellent visual outcome. These cases support the need for further clinical trials investigating the efficacy of LIT in hyperacute CRAO. Case 1 A 72-year-old man with a history of hypertension and dyslipidemia underwent uncomplicated phacoemulsification with topical anesthesia in a tertiary Universityaffiliated center. At his postoperative assessment 2.5 hours later, central visual acuity was 20/60 in keeping with mild corneal edema and intraocular pressure (IOP) was normal at 18 mm Hg. Twenty minutes later, he returned stating that 383 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution the vision in the operated eye had suddenly gone black. He was assessed by his surgeon and at 1 hour after visual loss, acuity was bare light perception in the operated eye with a brisk relative afferent pupillary defect (RAPD). Fundoscopy appeared normal with no appreciable edema of the retina or optic nerve (Fig. 1). Macular optical coherence tomography (OCT) was normal and intravenous fluorescein angiography was limited by corneal edema, but showed small arteriolar caliber in the affected eye. A presumptive diagnosis of embolic CRAO was made and informed consent was obtained to proceed with administration of LIT into the ophthalmic artery. The ophthalmic artery was cannulated by an interventional radiologist 2.75 hours after the onset of vision loss. One minute after administration of LIT, vision had improved to at least counting fingers, and his RAPD completely resolved. Central acuity had improved to 20/ 40 the following morning and retina appeared normal. Follow-up assessment at 1 week showed 20/20 vision. Embolic workup was performed. CT angiography of the chest, neck, and brain demonstrated only mild atherosclerotic disease in the bilateral internal carotid arteries. Transthoracic echocardiogram and 48 hour Holter monitor were normal. Case 2 A 47-year-old man with no known vascular risk factors underwent uncomplicated phacoemulsification with topical anesthesia in a community hospital. Near the end of the procedure, he felt his vision suddenly went dark. When this did not improve in the recovery room, he alerted his surgeon who assessed him and found his central acuity to be light perception with obvious RAPD in the operated eye. IOP was 13 mm Hg. At approximately 1 hour after vision loss, fundoscopy showed questionable retinal whitening. He was brought to the ophthalmology clinic and while there, he felt his vision improved slightly to count fingers. At 2 hours after vision loss, fundus photos confirmed retinal whitening, more dense in the inferior posterior pole and OCT of the macula showed diffuse central retinal edema (Fig. 2). Tertiary center neuro-ophthalmology service was contacted and with vision remaining at counting fingers at 2.75 hours after vision loss, the patient was transported by the family to be admitted for LIT. The ophthalmic artery was cannulated at approximately 5.5 hours after the onset of vision loss and LIT was administered. Vision began to improve a few minutes after LIT and after 1 hour, his central acuity was 20/100. Visual acuity was 20/25 at 4 day follow-up and retinal edema had resolved. MRI of the brain did not show any areas of restricted diffusion. Hypercoagulability workup was normal and CT angiography of the chest, neck, and brain did not show any significant atherosclerotic disease. Transthoracic echocardiogram and 48 hour Holter monitor were normal. He was started on a statin for newly diagnosed dyslipidemia. DISCUSSION Intravenous and local/intra-ophthalmic artery fibrinolysis have been investigated as a treatment for embolic CRAO. Existing evidence on retinal tolerance to ischemia (4,5) and current knowledge of the timing of intervention for cerebral infarctions suggest that the therapeutic window for treatment in short, likely only a few hours. A randomized control trial of intravenous fibrinolysis reported at least a 3-line gain of vision in 2 of 8 patients in the treatment group, both of whom received the intervention within 6 hours (7). Meta-analysis performed at the individual patient level for systemic fibrinolysis found that in 147 treated patients, 34 patients received treatment within 4.5 hours of vision loss and 17 (50%) had improvement of vision from 20/200 or worse to 20/100 or better. The authors concluded that this would be a reasonable window of eligibility for treatment in future randomized control trials (8). A retrospective case–control study of LIT administered to a cohort of 37 CRAO patients within 6 hours of vision loss found that 8 patients (22%) regained vision of at least 0.6 (20/33), where no patient in the control group of 19 FIG. 1. A. Fundus photo showing arteriolar attenuation and otherwise normal appearance of the retina and optic nerve 1 hour followed sudden vision loss. Fluorescein angiogram 2 minutes after dye injection (performed 1 hour after vision loss) (B) confirmed arteriolar attenuation and delayed filling. 384 Donaldson et al: J Neuro-Ophthalmol 2023; 43: 383-386 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. A. Fundus photo 2 hours following sudden vision loss showing arteriolar attenuation and macular edema and whitening, more dense inferiorly, with diffuse retinal thickening on OCT (middle panel) and preserved retinal laminar structure (bottom panel). B. Four days after LIT, retinal edema improved with resolution of retinal thickening and no inner retinal atrophy (middle, bottom panels). C. Angiography showing the left ophthalmic artery (white arrow), cannulated in the inset panel. OCT, optical coherence tomography; LIT, local intra-arterial thrombolysis. patients recovered vision to this extent (9). This was followed by a multicenter randomized control trial, the European Assessment Group for Lysis in the Eye (EAGLE) trial (10), in which LIT was compared with conservative management for patients with CRAO less than 20 hours duration. The results of this trial found no benefit for LIT; however, no patients received the intervention within 4 hours and only 3 patients received LIT in under 6 hours. A recent meta-analysis of LIT for CRAO in 219 patients found the odds ratio for vision improvement was significantly better with LIT only for patients treated within the first 6 hours (11). Both cases occurred in the cataract surgery peri-operative period. Although coincidental timing is possible, we hypothesize that fluctuations of intraocular pressure resulted in movement of small emboli distally until they became lodged in the central retinal artery. CRAO has been reported previously in association with intraocular surgery and has mainly been attributed to periorbital anesthesia (12) with 1 case series reporting ethylene oxide toxicity specifically in patients with posterior capsule rupture (13). The cases presented here occurred after routine, uncomplicated phacoemulsification using topical anesthetic with operative times under 20 minutes and normal IOP postoperatively. Absence of a visible retinal plaque is common and as a general rule, visible emboli confirm an embolic cause, but absence does not rule it out (14). Donaldson et al: J Neuro-Ophthalmol 2023; 43: 383-386 Spontaneous visual improvement does occur in some cases of CRAO when the occlusion is transient and visual prognosis is much better when there is a patent cilioretinal artery (1). In the 2 cases presented here, the decision was made to proceed with treatment because of the severity of vision loss with RAPD and evidence of poor macular perfusion on fluorescein angiogram (Case 1) and OCT of the macula (Case 2). Selection of appropriate candidates for LIT and for inclusion in future randomized control trials will be key because this treatment is not without potential morbidity or even mortality. Potential adverse effects include intracranial hemorrhage, which occurred in 2 of the 42 patients receiving LIT in the EAGLE trial. An ideal randomized control trial would include patients with severe vision loss treated within 6 hours of symptom onset and with noncalcified (15) embolic plaque. Timely diagnosis of CRAO is challenging as hyperacute retinal ischemia can have normal fundoscopy and OCT as was observed in Case 1. Primate studies have shown that appreciable retinal whitening is present within 1 hour after experimental clamping of the ophthalmic artery (16). Funduscopic changes took longer to develop in the cases presented here, apparent in the second case between 1 and 2 hours after vision loss. Although OCT of the retina showed grossly normal laminar structure, obvious retinal thickening was present in the affected eye. An increase in relative retinal thickness is the earliest OCT sign of CRAO, developing in 385 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution the first hours after ischemia onset before other signs such as hyper-reflectivity and loss of differentiation of the inner retina layers (17). The amount of retinal thickening allows for an approximation of the time since ischemia and may in future be used to determine whether patients are within a therapeutic window making them eligible for intervention (18). In summary, we describe 2 cases of hyperacute CRAO that were diagnosed and treated with LIT within 5.5 hours of visual loss, as both occurred in the immediate postoperative period after uncomplicated cataract surgery. Both cases demonstrated dramatic visual recovery, emphasizing the importance of early diagnosis of CRAO and effectiveness of LIT for CRAO if it is administered in the appropriate therapeutic window. The need for CRAO to be recognized as a medical emergency amenable to treatment in the same way as cerebral ischemia is increasingly being emphasized by the neuro-ophthalmology community (19). Wider recognition of this was reflected in a 2021 statement by the American Heart Association highlighting potential benefits of thrombolysis in CRAO and calling for more effective diagnosis and triage of this condition (20). CONCLUSIONS Patients presenting with recent onset of severe acute visual loss represent an ophthalmic emergency because they may be harboring an acute CRAO. CRAO maybe effectively treated with LIT when an appropriately trained interventional neuro-radiology team is available 24 hours a day to perform emergency treatment. STATEMENT OF AUTHORSHIP Conception and design: E. Margolin, L. Donaldson, P. Nicholson; Acquisition of data: E. Margolin, L. Donaldson, P. Nicholson; Analysis and interpretation of data: E. Margolin, L. Donaldson, P. Nicholson. Drafting the manuscript: E. Margolin, L. Donaldson, P. Nicholson; Revising the manuscript for intellectual content: E. Margolin, L. Donaldson, P. Nicholson. Final approval of the completed manuscript: E. Margolin, L. Donaldson, P. Nicholson. REFERENCES 1. Hayreh SS, Zimmerman MB. Central retinal artery occlusion: visual outcome. Am J Ophthalmol. 2005;140:376.e1–376.e. 2. Arruga J, Sanders MD. Ophthalmologic findings in 70 patients with evidence of retinal embolism. Ophthalmology. 1982;89:1336–1347. 3. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol. 1998;125:509–520. 4. Hayreh SS, Zimmerman M, Kimura A, Sanon A Central retinal artery occlusion. Exp Eye Res. 2004;78:723–736. 386 5. Tobalem S, Schutz JS, Chronopoulos A. Central retinal artery occlusion-rethinking retinal survival time. BMC Ophthalmol. 2018;18:101. 6. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Jauch CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Becker K, Southerland AM, Summers DV, Tirschwell DL. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50:e344–e418. 7. Chen CS, Lee AW, Campbell B, Lee T, Paine M, Fraser C, Grigg J, Markus R. Efficacy of intravenous tissue-type plasminogen activator in central retinal artery occlusion: report from a randomized, controlled trial. Stroke. 2011;42:2229–2234. 8. Schrag M, Youn T, Schindler J, Kirshner H, Greer D. Intravenous fibrinolytic therapy in central retinal artery occlusion a patient-level meta-analysis. JAMA Neurol. 2015;72:1148–1154. 9. Arnold M, Koerner U, Remonda L, Nedeltchev K, Mattle HP, Schroth G, Sturzenegger M, Weber J, Koerner F. Comparison of intra-arterial thrombolysis with conventional treatment in patients with acute central retinal artery occlusion. J Neurol Neurosurg Psychiatry. 2005;76:196–199. 10. Schumacher M, Schmidt D, Jurklies B, Gall C, Wanke I, Schmoor C, Maier-Lenz H, Solymosi L, Brueckmann H, Neubauer AS, Wolf A, Feltgen N. Central retinal artery occlusion: local intra-arterial fibrinolysis versus conservative treatment, a multicenter randomized trial. Ophthalmology. 2010;117:1367–1375.e1. 11. Hu H, Zhang B, Zhao Y, Zhou H, Chen H, Yan S. Efficacy of intra-arterial thrombolysis for acute central retinal artery occlusion: a meta-analysis. Eur Neurol. 2022;85:186–194. 12. Yusuf IH, Fung THM, Wasik M, Patel CK. Transient retinal artery occlusion during phacoemulsification cataract surgery. Eye (Lond). 2014;28:1375–1379. 13. Sen A, Mitra A, Tripathi S, Sharma M, Shenoy P. A cluster of central retinal artery occlusions following cataract surgery. Indian J Ophthalmol. 2019;67:630–633. 14. Hayreh SS, Zimmerman MB. Fundus changes in central retinal artery occlusion. Retina. 2007;27:276–289. 15. Gokhale S, Lahoti S, Rojas R, Caplan LR. Tissue plasminogen activator and calcific emboli. JAMA Neurol. 2013;70:642–643. 16. Hayreh SS, Weingeist TA. Experimental occlusion of the central artery of the retina. I. Ophthalmoscopic and fluorescein fundus angiographic studies. Br J Ophthalmol. 1980;64:896–912. 17. Ochakovski GA, Wenzel DA, Spitzer MS, Poli S, Härtig F, Fischer MD, Dimopoulos S, Schultheiss M. Retinal oedema in central retinal artery occlusion develops as a function of time. Acta Ophthalmol. 2020;98:e680–e684. 18. Wenzel DA, Kromer R, Poli S, Steinhorst NA, Casagrande MK, Spitzer MS, Schultheiss M. Optical coherence tomographybased determination of ischaemia onset—the temporal dynamics of retinal thickness increase in acute central retinal artery occlusion. Acta Ophthalmol. 2021;99:e247–e252. 19. Dumitrascu OM, Newman NJ, Biousse V. Thrombolysis for central retinal artery occlusion in 2020: time is vision. J Neuroophthalmol. 2020;40:333–345. 20. mac Grory B, Schrag M, Biousse V, Furie KL, Gerhard-Herman M, Lavin PJ, Sobrin L, Tjoumakaris SI, Weyand CM, Yaghi S, American Heart Association Stroke Council; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Hypertension; and Council on Peripheral Vascular Disease. Management of central retinal artery occlusion: a scientific statement from the American Heart Association. Stroke. 2021;52:e282–e294. Donaldson et al: J Neuro-Ophthalmol 2023; 43: 383-386 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.