Thrombolysis for Central Retinal Artery Occlusion in 2020: Time Is Vision!

Background: Acute nonarteritic central retinal artery occlusion (CRAO) is an eye stroke with poor visual prognosis and no proven effective therapies. Given advances in acute stroke care, thrombolysis in CRAO merits critical re-examination. We review the evidence for intravenous (IV) and intra-arterial (IA) tissue plasminogen activator (tPA) in CRAO management. Evidence acquisition: MEDLINE, Scopus, and Cochrane online databases were systematically searched from 1960 to present, for reports of acute IV or IA therapy with alteplase or tenecteplase in nonarteritic CRAO patients. English language case reports, case series, interventional studies, or randomized controlled trials were included. The study type, age and number of subjects, the regimen administered, the time since symptoms' onset, visual outcome, and safety reports were noted. Results: Use of IV thrombolysis with alteplase was reported in 7 articles encompassing 111 patients, with 54% of them receiving IV tPA within 4.5 hours of symptom onset, and none developing symptomatic intracranial or ocular hemorrhage. Six studies described IA alteplase administration, with only 18 of a total of 134 patients (13.4%) treated within the first 6 hours after visual loss. The reported adverse events were minimal. Visual outcomes post-IV and IA thrombolysis were heterogeneously reported; however, most studies demonstrated benefit of the respective reperfusion therapies when administered very early. We found no reports of tenecteplase administration in CRAO. Conclusions: In 2020, nonarteritic CRAO patients should theoretically receive the same thrombolytic therapies, in the same time window, as patients with acute cerebral ischemia. Eye stroke and teleeye stroke code encounters must include an expert ophthalmologic evaluation to confirm the correct diagnosis and to evaluate for ocular signs that may help guide IV tPA administration or IA management. Future research should focus on developing feasible retinal penumbra imaging studies that, similar to cerebral tissue viability or perfusion imaging, can be incorporated into the thrombolysis decision-making algorithm.

Disease of the Year: Cerebrovascular Disorders Section Editors: Valerie Biousse, MD Koto Ishida, MD Thrombolysis for Central Retinal Artery Occlusion in 2020: Time Is Vision! Oana M. Dumitrascu, MD, MSc, Nancy J. Newman, MD, Valérie Biousse, MD Background: Acute nonarteritic central retinal artery occlusion (CRAO) is an eye stroke with poor visual prognosis and no proven effective therapies. Given advances in acute stroke care, thrombolysis in CRAO merits critical reexamination. We review the evidence for intravenous (IV) and intra-arterial (IA) tissue plasminogen activator (tPA) in CRAO management. Evidence Acquisition: MEDLINE, Scopus, and Cochrane online databases were systematically searched from 1960 to present, for reports of acute IV or IA therapy with alteplase or tenecteplase in nonarteritic CRAO patients. English language case reports, case series, interventional studies, or randomized controlled trials were included. The study type, age and number of subjects, the regimen administered, the time since symptoms' onset, visual outcome, and safety reports were noted. Results: Use of IV thrombolysis with alteplase was reported in 7 articles encompassing 111 patients, with 54% of them receiving IV tPA within 4.5 hours of symptom onset, and none developing symptomatic intracranial or ocular hemorrhage. Six studies described IA alteplase administration, with only 18 of a total of 134 patients (13.4%) treated within the first 6 hours after visual loss. The reported adverse events were minimal. Visual outcomes post-IV and IA thrombolysis were heterogeneously reported; however, most studies demonstrated benefit of the respective reperfusion therapies when administered very early. We found no reports of tenecteplase administration in CRAO. Conclusions: In 2020, nonarteritic CRAO patients should theoretically receive the same thrombolytic therapies, in the same time window, as patients with acute cerebral ischeDepartment of Neurology (OMD), Cedars-Sinai Medical Center, Los Angeles, California; and Departments of Ophthalmology (NJN, VB), Neurology (NJN, VB), and Neurological Surgery (NJN), Emory University School of Medicine, Atlanta, Georgia. V. Biousse has received research support from the NIH/NEI core grant P30-EY006360 (Department of Ophthalmology) and from the NIH/PHS (UL1-RR025008). V. Biousse is a consultant for GenSight Biologics. N. J. Newman has received research support from the NIH/NEI core grant P30-EY006360 (Department of Ophthalmology) and from the NIH/PHS (UL1-RR025008). N. J. Newman is a consultant for GenSight Biologics, Santhera, and Stealth Pharmaceuticals. The remaining author reports no conflicts of interest. Address correspondence to Oana M. Dumitrascu, MD, MSc, Department of Neurology, Cedars-Sinai Medical Center, 127 S. San Vicente Boulevard, A6302, Los Angeles, CA 90048; E-mail: oana.m. [e-mail] Dumitrascu et al: J Neuro-Ophthalmol 2020; 40: 333-345 mia. Eye stroke and teleeye stroke code encounters must include an expert ophthalmologic evaluation to confirm the correct diagnosis and to evaluate for ocular signs that may help guide IV tPA administration or IA management. Future research should focus on developing feasible retinal penumbra imaging studies that, similar to cerebral tissue viability or perfusion imaging, can be incorporated into the thrombolysis decision-making algorithm. Journal of Neuro-Ophthalmology 2020;40:333-345 doi: 10.1097/WNO.0000000000001027 © 2020 by North American Neuro-Ophthalmology Society C entral retinal artery occlusion (CRAO) is an ophthalmologic and neurologic emergency, with an incidence of 1 per 100,000 in a single-county US population (1), increasing with age to 7-10 per 100,000 in Koreans above 65 years (2), and 5.8/100,000 person-years increasing to 57/100,000 person-years at the age of 80-84 years in Germany (3). Occlusion of the central retinal artery (CRA) leads to acute retinal infarction, which classifies CRAO as an acute carotid circulation ischemic stroke syndrome (4). The American Heart Association (AHA) defines central nervous system infarction as brain, spinal cord, or retinal cell death attributable to ischemia, based on pathological, imaging, and/or clinical evidence (5). Despite retinal infarction being clearly recognized as comparable with brain infarction and the undisputable adoption of thrombolysis as a standard of care therapy for brain acute ischemic stroke (AIS) syndromes (6), controversy still remains regarding the net benefit of acute reperfusion therapies in CRAO. One major concern relayed by numerous reports is the lack of patients' presentation in specialized stroke centers or emergency departments (EDs) in the currently accepted time window for stroke thrombolysis (within 4.5 hours for intravenous [IV] alteplase and 6 hours for intra-arterial thrombolysis [IAT]) (7-10). Patients with isolated visual loss usually present to eye care providers, and studies show that only about one-third of ophthalmologists transfer acute CRAO patients to an ED for immediate evaluation 333 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders (11,12). In a US 2013 survey (13), only 18% of vitreoretinal specialists compared with 75% of neurologists reported that they would recommend admission to a stroke unit or ED referral for an acute embolic CRAO. However, a 2018 national survey (14) revealed that more than half of US academic centers offer IV tissue-type plasminogen activator (tPA) to select CRAO patients who present at early time points, and tPA was the preferred initial treatment in 36% of cases. It is currently recommended that ophthalmologists recognize the paradigm for CRAO management has changed (15,16). Most recently, the American Academy of Ophthalmology (AAO)-endorsed preferred practices highlight that acute symptomatic CRAO should prompt an immediate referral to the nearest stroke referral center for prompt assessment for consideration of an acute intervention (17). The variety of multiple fibrinolytic agents in various CRAO studies and their amalgamation in systematic reviews and meta-analyses (9,10,18,19) has led to conclusions that differ from the current AIS standard management practices that exclusively endorse alteplase or tenecteplase for reperfusion therapy and do not recommend other fibrinolytic agents (6). The focus of this review is to provide an update on the best recent evidence for acute thrombolytic therapy in nonarteritic CRAO. We propose practical recommendations for the management of these patients, specifically geared toward the indication, benefits, risks, and time window of IV and IA thrombolysis with tPA. ACUTE RETINAL ARTERIAL ISCHEMIA PATHOPHYSIOLOGY Patients with CRAO present with acute monocular visual loss and have a guarded prognosis, most developing severe and permanent monocular visual loss (18,20-22). CRAO is bilateral in 1%-2% of cases (23) and has a nonarteritic etiology in 95% of cases (24). The more rare arteritic form (usually secondary to giant cell arteritis) will not be addressed in this review; however, it needs to be considered in any patient older than 50 years with acute retinal ischemia and absence of emboli on funduscopic examination, especially if headaches or systemic symptoms of giant cell arteritis coexist. Nonarteritic cases are most commonly secondary to embolic or prothrombotic disorders, and less frequently to perioperative (25-27), dental or facial surgical procedures (28). The most common cause of nonarteritic CRAO is a proximal embolus deriving from the ipsilateral carotid artery, aortic arch, or heart (22). The embolus composition is variable; the platelet-fibrin-cholesterol emboli originating from the carotid arteries, heart valves, or the aortic arch being encountered most frequently, followed by thrombotic emboli related to atrial fibrillation and, rarely, calcified emboli originating from calcified cardiac valves (29). 334 The CRA originates from the ophthalmic artery (OA), bifurcates into the superior and inferior branches on the optic disc and supplies the inner retinal layers, including the macula and fovea. In 15%-30% of the population, a cilioretinal artery originates from the posterior ciliary circulation directly from the OA and provides blood supply to the macula (30,31). The outer retinal layers are supplied from the choroidal arterial network that also derives from the OA. A dual anastomotic network supplies the OA as follows: a deep network incorporating the internal maxillary artery and anterior temporal artery, and a superficial network incorporating the dorsal nasal artery and the facial artery (32). The retinal arteries are considered "end-arteries" because their distal intraneural and intraocular portions do not exhibit arterio-arterial anastomoses (33). The CRA diameter at the optic nerve head is approximately 160 mm, and the narrowest portion of the CRA is about 2 mm behind the globe at the level of the lamina cribrosa. Large emboli likely lodge at this narrowest point, explaining why not all embolic CRAOs have visible retinal arterial emboli on funduscopic examination. RETINAL PENUMBRA TIMING Preclinical animal studies in rhesus monkeys indicate that irreversible damage to the retina from ischemia likely occurs in less than 240 minutes from the onset of experimental CRAO (34). Shorter retinal ganglion cell survival times in the setting of perfusion deprivation have since been suggested (33,35). Retinal thickness measured using optical coherence tomography may be used to quantify retinal edema in acute CRAO, which correlates with the time elapsed since the retinal ischemia onset (36). Despite lack of definitive data on human retinal penumbra timing, by analogy with cerebral ischemia affecting small "end-arteries," it is likely that thrombolytic administration up to 4.5 hours (270 minutes) from symptom onset will help retinal reperfusion. Recent acute stroke trials for cerebral ischemia have suggested that the treatment window may be even longer in patients with ischemic but not yet infarcted brain tissue on perfusion or multimodal MRI and that selection of stroke patients for reperfusion therapies on the basis of tissue viability rather than time from onset of stroke may result in better outcomes (37-42). Although waiting for further guidance from ongoing cerebral ischemia clinical trials, additional animal and human studies evaluating the retinal ischemia tolerance time and perfusion maps are similarly warranted. ACUTE RETINAL ARTERIAL ISCHEMIA NATURAL HISTORY: VISUAL OUTCOMES The natural history of CRAO is highly variable because it depends on the degree of arterial occlusion and collateral circulation. Although spontaneous recovery is described Dumitrascu et al: J Neuro-Ophthalmol 2020; 40: 333-345 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders (43,44), overall less than 10% of patients report a meaningful recovery of vision (18). Hayreh et al (45) reported spontaneous visual acuity (VA) improvement in 22% of eyes with nonarteritic CRAO, with a final VA of 20/400 or worse in 61%. However, it is likely that a number of acute CRAOs recover spontaneously within a few hours of visual loss and are not diagnosed or underreported. The central VA can be near normal in CRAO patients with a cilioretinal artery (20/50 or better) (46), although the peripheral vision usually remains severely impaired (45,47). Overall, CRAOrelated visual morbidity is associated with poor mental health (48), decreased quality of life, and possibly institutional care (49). nolysis," "intravenous," "intra-arterial," "alteplase," "tenecteplase," "tPA," and "retinal artery occlusion." Relevant articles were reviewed for content and significance. Case reports, case series, interventional studies, or randomized controlled trials (RCTs) of patients with acute-onset nonarteritic CRAO who were administered IV or IA alteplase were included. We excluded patients that received fibrinolytic agents other than tPA, single case reports, reviews, meta-analyses, CRAO of vasculitic etiology, and nonEnglish language articles. We recorded the study type, age and number of subjects that received alteplase, the regimen administered, the time since symptoms onset, visual outcomes, and safety reports. ACUTE RETINAL ARTERIAL ISCHEMIA NATURAL HISTORY: VASCULAR RISKS INTRAVENOUS THROMBOLYSIS WITH TENECTEPLASE Acute retinal ischemia morbidity is augmented by its association with an increased systemic vascular risk (16). In the European Assessment Group for Lysis in the Eye (EAGLE) study, previously undiagnosed vascular risk factors were found in 78% of all CRAO patients, with arterial hypertension, coronary artery disease, atrial fibrillation, and valvular heart disease found in 73%, 22%, 20% and 17% of patients, respectively (50). Another CRAO cohort that underwent methodical risk factor screening demonstrated 36.7% of patients had critical carotid disease, 37.3% coincident acute stroke, 33.0% hypertensive emergency, and 20.0% myocardial infarction or critical structural cardiac disease (51). Of 1,7117 CRAO inpatient admissions in the United States between 2003 and 2014, the incidence of in-hospital stroke was 12.9%. Female sex, hypertension, carotid artery stenosis, aortic valve disease, smoking, and alcohol use were positive predictors of in-hospital stroke (52). Multiple recent studies report that up to 53% of patients with acute CRAO have concurrent acute small, often asymptomatic, cerebral infarctions on diffusion-weighted imaging (DWI-MRI) (16,53-55) at the time of presentation, supporting the need to respect the very short time windows recommended for the treatment of brain ischemia even in patients with clinically isolated CRAO. Similarly, cardiovascular morbidity and mortality (vascular death or myocardial infarction) after a CRAO are higher than in the general population (11,50,56). Tenecteplase, a newer thrombolytic agent, has the advantage of easier administration than alteplase by using a single IV bolus, higher fibrin specificity, and longer half-life. A recent metaanalysis demonstrated evidence of noninferiority to alteplase, leading to a level of evidence IIb for tenecteplase in select patients with brain AIS, such as those eligible for mechanical thrombectomy or with minor neurological impairment and no proximal large vessel occlusion (6,57). In the absence of tenecteplase approval by the Food and Drug Administration for cerebral ischemia as of yet, and scientific reports of its efficacy and safety in CRAO, specific endorsements cannot be currently made in this regard. THROMBOLYSIS IN CENTRAL RETINAL ARTERY OCCLUSION: LITERATURE SEARCH We reviewed the scientific literature to date for studies reporting acute IV or IA therapy with alteplase or tenecteplase in CRAO. Ovid MEDLINE/PubMED, Scopus, and the Cochrane online databases were systematically queried from 1960 to present, using the following MeSH (Medical Subject Headings) words: "thrombolysis," "fibriDumitrascu et al: J Neuro-Ophthalmol 2020; 40: 333-345 INTRAVENOUS THROMBOLYSIS WITH ALTEPLASE Our literature search identified 7 articles, beginning in 1995 with a report of 2 cases (58), 4 prospective interventional studies (59-62) with a total of 71 patients, one retrospective analysis of 30 patients (63), and one phase II placebocontrolled RCT that was terminated prematurely after enrolling 8 patients in the thrombolysis group (7) (Table 1). Of a total of 111 patients, only 60 (54%) received IV alteplase within 4.5 hours of symptom onset. Intravenous Thrombolysis Protocol and Side effects Other than the 2 case reports in which the alteplase dosage was unspecified (58), and the Hattenbach et al (60) Case series that used 50 mg, all other studies used the same dose of IV alteplase, that is, currently recommended for acute cerebral ischemia (Table 2), 0.9 mg/kg IV (maximum of 90 mg, with a 10% bolus over 1 minute, followed by the remaining dose over 1 hour). IV heparin was started at 1,200 units per hour concomitant with IV alteplase and continued over 5 days as monitored by activated partial thromboplastin time (aPTT; target range, 60-80 seconds) in 28 patients in Hattenbach et al's (60) study and no hemorrhagic 335 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders TABLE 1. Large studies evaluating intravenous thrombolysis in central retinal artery occlusion patients Author, Year, Country No. Subjects, Age (yrs) Study Type Thrombolytic Regimen Time of tPA Administration Since Onset/Last Known Well (h) 2.75 and 4 No complications 2-18 (6 pts within 4.5 h) At 3rd d, 10/12 pts improved VA. 4/10 pts improved VA .8 Snellen lines. 4/6 treated within 4.5 h improved VA. No complications 50 mg IV tPA over 60 min Concomitant IV heparin (1,200 units/h, continued over 5 d as monitored by aPTT: target range 60-80 sec) 1.5-12 (7 pts within 4.5 h) At a mean follow-up of 2.2 mo (range 1-4 mo), 9 eyes improved VA $3 Snellen lines. 18 eyes unchanged. 1 eye worse (loss of 3 or more Snellen VA lines). No complications 0.9 mg/kg IV tPA (max 90 mg, with 10% IV bolus and the remainder over 1 h) 0.9 mg/kg IV tPA (max 90 mg, with 10% IV bolus and the remainder over 1 h) Mean 14.4 ± 6.5 (1 pt within 4.5 h) At 1 wk, 2/8 pts improved VA $3 Snellen lines. At 3 mo, 0/8 improved VA $3 Snellen lines. 1 ICH 1 vitreous hemorrhage (CNV) Median 4.25 (range 1.75-10.5) (7 pts within 4.5 h) All 4 pts with a negative spot sign had VA 30/ 32 or better (logMAR # 0.2) and restored blood flow. All 7 pts with a positive spot sign had VA 20/ 1,000 or worse (logMAR $1.7) and persistent occluded arteries.* No complications Mean 4.55 ± 1.05 (17 pts within 4.5 h) At 1 mo, 16/30 had significant VA improvement (defined as a decrease of 0.3 logMAR). 1 symptomatic ICH (alteplase and IV heparin) 2 asymptomatic ICH 1 hematuria At Day 5, VA improved from baseline mean log-MAR 2.46 ± 0.33 (20/5,700 Snellen equivalent) to 1.52 ± 1.09 (20/660 Snellen equivalent) (P = 0.002). At Day 30, logMAR VA was 1.60 ± 1.08 (20/ 800 Snellen equivalent) (vs Baseline P = 0.004, vs Day 5 nonsignificant). 1 angioedema 1 bleeding from abdominal aortic aneurysm 2 (74 and 61) Case reports tPA dose not mentioned. Kattah et al (59), 2002, USA 12 (range 53-89) Prospective 0.9 mg/kg IV tPA (max 90 mg, 10% IV bolus and the remainder over 1 h) 9/12 also had paracentesis Hattenbach et al (60), 2008, Germany 28 (range 30-85) Prospective interventional case series Chen et al (7), 2011, Australia 8 (mean 73 ± 8) Phase II, placebocontrolled RCT Nedelmann et al (61), 2015, Germany 11 (age range not specified) Prospective interventional case series 30 (mean 62.5 ± 15.1) Schultheiss et al (62), 2018, Germany 20 (mean 72.8 ± 10.9) Retrospective analysis Prospective interventional case series Safety Reports At 96 h, 1 pt improved VA .8 Snellen lines. 1 pt improved VA .4 Snellen lines. Mames et al (58), 1995, USA Preterre et al (63), 2017, France Visual Outcome 0.9 mg/kg IV tPA (max 90 mg, with 10% IV bolus and the remainder over 1 h) 0.9 mg/kg IV tPA (max 90 mg, with 10% IV bolus and the remainder over 1 h) Median 3.5 (IQR 2-4: 20 pts treated within 4.5 h) *The time point for posttreatment visual acuity measurement was not specified. aPTT, activated partial thromboplastin time; CNV, choroidal neovascular membrane; GI, gastrointestinal; ICH, intracranial hemorrhage; IQR, interquantile range; logMAR, logarithm of the minimum angle of resolution; PT, prothrombin time; Pt, patient; pts, patients; RCT, randomized controlled trial; VA, visual acuity; IV, intravenous. complications were noted. However, in Preterre et al's (63) retrospective analysis, one symptomatic intracranial hemorrhage (ICH) occurred in a subject in whom IV heparin was started just after alteplase administration, which constitutes a protocol violation as per the current AHA guidelines (Table 2). In the same series, 2 patients (6.7%) had asymptomatic ICH and 1 patient had hematuria, but it is not clear whether 336 these patients received alteplase as per the current cerebral ischemia protocol or not (63). In the only RCT conducted to date (7), the mean time of IV tPA administration was 14.4 ± 6.5 hours from symptom onset. Only one patient received alteplase at 4.5 hours, and one was treated at 6 hours. Likely due to delayed alteplase administration, 1 patient had ICH 45 minutes Dumitrascu et al: J Neuro-Ophthalmol 2020; 40: 333-345 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders TABLE 2. Intravenous thrombolysis as per the 2019 American Heart Association Acute Ischemic Stroke Guidelines (Powers et al, 2019) (6) Before IV Alteplase Patient eligibility determination are as follows: Less than 4.5 h since symptoms' onset/last seen normal. Disabling stroke-related deficit. No contraindications* Conduct a risk-benefit discussion in a timely manner. Treat high BP Goal BP ,185/110 mm Hg. Treat blood sugar less than 50 mg/ dL or greater than 400 mg/dL. Perform and document TIME-OUT (identification of patient and weightbased alteplase dosage and inclusion and exclusion criteria). IV Alteplase Protocol After IV Alteplase 0.9 mg/kg Maximum dose 90 mg over 60 min, with initial 10% of dose given as a bolus over 1 min, followed by 90% as infusion. Vital signs and neuro checks Q15 min for 2 h, followed by Q30 min for 6 h, then Q1 h for up to 24 h. Maintain BP ,180/105 mm Hg If patient develops severe headache, acute hypertension, nausea, vomiting, or worsening neurological examination, discontinue IV alteplase infusion and obtain emergent brain CT. Avoid antithrombotic agents for 24 h; obtain follow-up brain CT or MRI at 24 h after IV alteplase before starting anticoagulants or antiplatelet agents. Delay placement of nasogastric tubes, indwelling bladder catheters, or intra-arterial pressure catheters if the patient can be safely managed without them. Admission to the stroke unit or intensive care unit for 24 hclose monitoring, using standardized stroke care order sets. *Contraindications to intravenous alteplase are as follows: 1) radiological contraindications are as follows: acute intracranial hemorrhage on head CT; early ischemic changes greater than mild-moderate extent or frank hypodensity on head CT; and greater than 10 cerebral microbleeds on brain MRI (if acute MRI is performed instead of CT or previous MRI available for review) in which case IAT may be used instead of IV alteplase within 6 hours. 2) clinical contraindications are as follows: greater than 4.5 hours since symptoms' onset/last seen normal; received a full treatment dose of low-molecular-weight heparin (LMWH) within the previous 24 h; BP .185/110 mm Hg; history of warfarin use and INR $1.7 or PT .15 seconds; previous ischemic stroke within 3 months; severe head trauma within 3 months; posttraumatic infarction that occurs during the acute in-hospital phase; intracranial/spinal surgery within the previous 3 months; history of intracranial hemorrhage; structural GI malignancy or recent bleeding event within 21 days; taking direct thrombin inhibitors or direct factor Xa inhibitors unless laboratory tests, such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a dose of these agents for .48 hours (assuming normal renal metabolizing function); symptoms consistent with infective endocarditis; known or suspected aortic arch dissection; and intra-axial intracranial neoplasm. 3) laboratory contraindications are as follows: platelet count ,100,000/mm3; INR .1.7; PT .15 seconds; and aPTT .40 seconds. 4) ophthalmologic contraindications to intravenous alteplase are as follows: hemorrhagic diabetic retinopathy; active choroidal neovascularization (wet age-related macular degeneration); and vitreous or preretinal hemorrhage. aPTT, activated partial thromboplastin time; BP, blood pressure; CT, computed tomography; IV, intravenous; IAT, intra-arterial thrombolysis; INR, international normalized ratio; Q, every. after tPA infusion and a modified Rankin score of 2 at discharge. There were no retinal or systemic acute hemorrhages, but 1 patient had delayed retinal neovascularization and vitreous hemorrhage. Largely, IV alteplase in acute CRAO seems to be safe because none of the 60 cases that received IV alteplase within 4.5 hours of symptom onset developed symptomatic ICH or ocular hemorrhage. One angioedema, one bleeding from an abdominal aortic aneurysm, (62) and one episode of hematuria (63) were reported in patients treated within 4.5 hours. Visual Outcomes After Intravenous Thrombolysis In Chen et al's (7) RCT, 2 patients treated with alteplase at 4.5 and 6 hours had VA improvement of 3 Snellen lines or Dumitrascu et al: J Neuro-Ophthalmol 2020; 40: 333-345 more at 1 week after treatment vs none of the placebo group. VA improvement of these 2 patients was not sustained at 6 months. In the Kattah et al (59) series, VA improved in 4 of the 6 (66%) patients who received alteplase within 4.5 hours, whereas 83.3% of patients had better vision overall. In the Hattenbach et al (60) and Preterre et al (63) series, significant VA improvement occurred in 32% and 55.2% of patients, respectively. Similarly, significant improvement early at Day 5 and later at Day 30 was noted in the prospective interventional series of 20 patients that received alteplase within the first 4.5 hours after symptoms onset (62). Interestingly, Nedelmann et al (61) stratified the patients' responses based on the presence of a spot sign (a hyperechoic structure in the CRA on B-mode ocular ultrasound). They noted that all 4 patients with absent 337 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders retrobulbar spot sign had significant visual improvement (VA 20/32 or better) and restored blood flow on Doppler ultrasound, whereas all 7 spot-sign positive patients had persistent visual impairment (VA 20/1,000 or worse), and their arteries remained occluded. As an intra-arterial spot sign may be suggestive of a calcified component of the occlusive embolus, the authors suggested inclusion of ocular sonography in future studies to detect a potential subgroup less amenable to IV alteplase (61). INTRA-ARTERIAL THROMBOLYSIS WITH ALTEPLASE Mechanical thrombectomy is considered standard of care for patients with brain AIS and proximal large vessel occlusion, with recent expansion of the time window in selected patients up to 24 hours (6). Although IAT initiated within 6 hours of stroke onset in carefully selected patients who have contraindications to the use of IV alteplase is a consideration, it is not a standard practice as the consequences of the intervention are unknown, according to the most current AHA recommendations (6). Patients with CRAO are not candidates for mechanical thrombectomy given a distal embolus and low CRA diameter (64,65). However, microcatheterization of the OA or other collateral vessels in cases with difficult direct access to the OA allows for in situ administration of intra-arterial thrombolytics (8). Potential advantages of IAT are reduction of total thrombolytic dosage administered and extension of time window to 6 hours after symptom onset (Fig. 1). Unfortunately, IAT can only be administered in select centers (Thrombectomy-Capable or Comprehensive Stroke Centers) with experienced interventionalists. Our literature search for reports of selective IAT with tPA identified a small series of 3 cases (66), 4 retrospective case series, including a total of 89 patients (67-70), and the EAGLE RCT (8) that enrolled 42 patients in the IAT arm (Table 3). Overall, excluding the Mercier et al (70) series that reports no time-specific data, only 18 of the 134 (13.4%) patients received IAT within 6 hours. Intra-arterial Thrombolysis Protocol and Side Effects The duration of tPA infusion was variable, and tPA was administered either continuously or in aliquots. The dosage of tPA administration varied between 8.8 and 80 mg, with lower dosages when administered using aliquots (69). Most studies reported heparin administration in addition to tPA. A wide spectrum of times of tPA injection from symptom onset was seen, with a mean of 8.07 (SD 3.34) hours in all case series and 12.7 (SD 5.77) hours in the RCT (8). Most interventionalists administered tPA selectively into or at the origin of the OA and used the external carotid artery or middle meningeal artery when OA access was impossible (such as in cases with severe internal carotid artery stenosis 338 or occlusion). In addition to delayed presentation, IAT studies underscored that the endovascular option further delayed retinal reperfusion. For instance, although the mean time to presentation to a comprehensive stroke center was 3.3 ± 2.0 hours, the mean time from the onset of visual loss to IAT was 9.3 ± 2.9 hours in the Aldrich et al (69) case series. Notably, all IAT in CRAO reports were published before the positive AIS endovascular trials that mandated changes in AIS management systems of care. In this era of optimized infrastructure for interventions, the time to groin puncture is likely better if the interventional team is notified in a timely manner. Overall, minimal safety concerns were reported as follows: of the 134 patients, 2 transitory ischemic attacks, 2 ICHs, 1 hypertensive crisis, and 2 groin hematomas were reported. In addition, minor adverse reactions were described in 12 patients in the EAGLE RCT (8). No patient had long-term complications. It remains unclear if the reported side effects are related to the dosage of tPA, duration of tPA administration, the procedure, time elapsed since symptom onset, or if patients had concomitant silent cerebral ischemia that may have predisposed them to complications from thrombolytic therapy. Visual Outcomes After Intra-arterial Thrombolysis Although the degree of visual recovery post-IAT was heterogeneously reported regarding the VA scale and the timing of follow-up measurements, most studies demonstrated net benefit. The largest case series (67) showed that 35 of 53 patients (60%) had improved VA (25 patients, 2 Snellen lines or greater; 10 patients, 1-2 lines), consistent with a significant increase in VA compared with preoperative values (P , 0.0001). In Mercier et al's (70) retrospective case series, 6 of 14 patients (43%) had significantly improved VA, superior or equal to 20/200, corresponding to an improvement of $0.3 logarithm of the minimum angle of resolution (logMAR). An irregular carotid siphon was noted in 2 cases and seemed to be a predictive factor of treatment failure. No correlation was found between VA improvement and the thrombolytic dose injected (P = 0.791). In Pettersen et al's (68) series, 50% of treated eyes (4 of 8) had improved VA at 24 hours and 75% at a final follow-up (range 1-33 months); however, no patient had VA better than 20/300 and all patients had residual monocular visual field defects. In Aldrich et al's (69) series, 15 of 21 patients (71.4%) had $1 Snellen line improvement in VA within 24 hours after completion of IAT vs 9.5% in the control group (P , 0.001). At final examination, 76.2% of subjects in the IAT group had an improvement in VA of one Snellen line or more (a mean follow-up, 15 months) vs 33.3% of controls (a mean follow-up, 11 months; P = 0.018). The only prospective multicenter RCT (8), designed as a clinical superiority trial, showed no difference Dumitrascu et al: J Neuro-Ophthalmol 2020; 40: 333-345 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders FIG. 1. Proposed acute management of patients with presumed acute central retinal artery occlusion (CRAO). 1) The diagnosis of acute CRAO must be confirmed before thrombolysis is administered. If patients present to an outpatient eye care center or other practitioner office with symptoms suggestive of acute CRAO, a 911 call should be initiated to facilitate patients' emergent transport to the closest facilities (e.g., Certified Stroke Center) that are able to administer intravenous (IV) alteplase, even if visual loss is isolated (without any neurologic symptoms). If patients present to an ED without access to acute stroke care, either in person or through telemedicine, emergent transfer to the closest Stroke Ready Center should be similarly arranged, using emergency medical services or the local hospital policy. In the ED or en route to the ED through a prehospital notification, "eye stroke code" activation should prompt emergent neurological and ophthalmological evaluations, either in person or through telemedicine. 2) Patients seen early enough to allow for administration of IV alteplase within 4.5 hours of vision loss should undergo the evaluation recommended by the American Heart Association (AHA) for brain acute ischemic stroke (Table 2). 3) Because of time constraint, the ophthalmologic evaluation should be limited to what is necessary to confirm the diagnosis of acute nonarteritic CRAO and rule out ocular contraindications to thrombolytic treatment, such as vitreous or retinal hemorrhage, hemorrhagic diabetic retinopathy, and active choroidal neovascularization (wet age-related macular degeneration). Because classic funduscopic signs of CRAO can be missing very acutely, we recommend macular optical coherence tomography to demonstrate thickening of the inner retinal layers secondary to retinal edema (81,82) to rapidly confirm the CRAO diagnosis if necessary. We do not recommend retinal fluorescein angiography that is time consuming and delays appropriate management. Baseline visual acuity should be documented, but formal visual field testing should be delayed until after treatment. Bedside evaluation is preferred for patients presenting to the ED, and funduscopic imaging with a nonmydriatic fundus camera should be obtained whenever possible (78). 4) If systemic contraindications for IV alteplase are identified, as per the 2019 AHA guidelines (6), intra-arterial thrombolysis (IAT) should be considered. A neuro-interventional specialist should be consulted early to discuss potential IAT. Computed tomography (CT) angiogram of head and neck should not delay the administration of IV alteplase but should be performed before IAT in all CRAO patients. CT angiography of the extracranial carotid arteries and intracranial circulation provides useful information on patient eligibility and endovascular procedural planning. Knowledge of vessel anatomy and presence of extracranial vessel dissection, stenosis, and occlusion may assist in planning endovascular procedures or identifying patients ineligible for treatment (6). Transfers to a Thrombectomy-Capable or Comprehensive Stroke Center should be emergently arranged if patients have an isolated CRAO within 6 hours of visual loss. 5) The patient counseling regarding the benefits and risks of IV and intra-arterial (IA) alteplase should incorporate the findings discussed in the abovementioned studies (Tables 1 and 3). The potential risks should be discussed during eligibility deliberation and weighed against the anticipated benefits during decision making (6),emphasizing the lack of randomized controlled trial proving alteplase efficacy in the treatment of CRAO. 6) After the acute thrombolytic intervention is pursued, all patients should be admitted to a stroke unit or intensive care unit (depending on an institutional protocol) for timely and targeted stroke secondary prevention, as all patients with presumed retinal ischemia (whether transient or permanent) should undergo urgent brain imaging and etiologic testing similar to patients with cerebral ischemia (16). BMP, basic metabolic profile; CBC, cell blood count; CRP, C-reactive protein; ED, emergency department; ESR, erythrocyte sedimentation rate; INR, international normalized ratio; NIHSS, National Institute of Health Stroke Scale; OCT, optical coherence tomography; PO, oral; PT, patient; PTT, partial thromboplastin time; RAPD, relative afferent pupillary defect. Dumitrascu et al: J Neuro-Ophthalmol 2020; 40: 333-345 339 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders TABLE 3. Large studies evaluating intra-arterial thrombolysis in central retinal artery occlusion patients Author, Year, Country No. Subjects, Age (yrs) Thrombolytic Regimen Catheter Placement for Thrombolytic Administration Study Type Padolecchia et al (66), 1999, Italy 3 (range 62-76) Case reports tPA 40-70 mg over 45-90 min Heparin 3,000 units and 1 wk LMWH Ophthalmic A (2 pts) MMA (1 pt) Richard et al (67), 1999, Germany 46 (mean 58 ± 16.4) (range 19-76) Retrospective case series Pettersen et al (68), 2005, Canada 8 (range 59-77) Retrospective case series Aldrich et al (69), 2008, USA 21 (mean 65.1 ± 13) Retrospective, singlecenter, nonrandomized interventional study of consecutive patients Schumacher et al (8), 2010, Austria and Germany 42 (mean 63 ± 10) Randomized, controlled, prospective, multicentric, clinical superiority trial tPA 10-20 mg over 3 h Heparin 5,000 units bolus, then 1,000 units/h Ophthalmic A tPA mean dose 15.8 mg (range 10-20), over 15-60 min Ophthalmic A tPA aliquots of 3 mg infused over 5 min each. Infusion stopped if clinical VA improvement or prespecified maximum dose of 20 mg tPA reached. Mean dose 11.25 ± 3.5 mg; infusion duration 96.32 ± 8.3 min Heparin 3,000 units Ophthalmic A tPA up to maximum of 50 mg. VA and fundus after injections of 15, 30, 45, and 50 mg. Heparin and aspirin Ophthalmic A External carotid artery in case of occlusion or high-grade stenosis of the ICA. Mercier et al (70), 2015, France 14 (mean 60.7) Retrospective case series Author, Year, Country Time of tPA Administration Since Onset/Last Known Well (h) tPA mean dose 35 ± 13 mg, infused over 40 min. Ophthalmic A Visual Outcome Safety Reports Padolecchia et al (66), 1999, Italy 4.5-6.5 (2 within 6 h) 1 pt with partial recovery (unspecified VA) at end of the procedure; sustained at 5 mo. 2 pts with complete recovery of VA at 5 mo. No complications Richard et al (67), 1999, Germany 14 ± 10 range 3-50 (11 within 6 h) At 3 mo, 35/53 pts improved VA, 25 pts $2 lines and 10 patients 1-2 lines. 12 pts with no improvement. 6 pts with worse VA. 2 transient mild hemiparesis 1 hypertensive crisis 340 Dumitrascu et al: J Neuro-Ophthalmol 2020; 40: 333-345 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders (Continued ) Author, Year, Country Time of tPA Administration Since Onset/Last Known Well (h) Pettersen et al (68), 2005, Canada 9.7 range 6-18 (1 at 6 h) Aldrich et al (69), 2008, USA Mean 9.3 ± 2.9 (0 within 6 h) Schumacher et al (8), 2010, Austria and Germany Mean 12.78 ± 5.77 range 4.75-23.43 (4 within 6 h) Mercier et al (70), 2015, France 8 (range 4-17) Visual Outcome At 24 h, 1/8 with VA improved by 2 Snellen lines, 3/8 with VA improved by 1 Snellen line, and 4/8 with unchanged VA. At final follow-up (range 1- 33 mo), 6/8 improved VA by $1 Snellen lines, and 2 lost to follow-up. At 24 h, 15/21 had VA improvement by $1 line and 6/21 had no change in vision. At final follow-up (mean 15.2 mo), 16/21 had VA improvement by $1 line, 4/21 had no change in VA, and 1/21 had worse VA by $1 line. At 1 mo, 24/40 had clinically significant visual improvement (defined as $0.3 logMAR) and 7/40 had logMAR $1.0. At either 6 or 12 mo, 6/14 had improvement of $0.3 on a logMAR scale Safety Reports No complications 2 groin hematomas 2 ICH 3 headache, dizziness 3 mild ICA vasospasm 2 eyelid edema 2 groin hematoma 1 IOP increase 1 troponin increase 1 tinnitus 1 postprocedural hemorrhage 1 epistaxis 1 oral hemorrhage 1 facial hyperesthesia No complications ICA, internal carotid artery; ICH, intracerebral hemorrhage; IOP, intraocular pressure; LMWH, low-molecular-weight heparin; logMAR, logarithm of the minimum angle of resolution; MMA, middle meningeal artery; pt, patient; pts, patients; VA, visual acuity. in change of logMAR between standard therapy (combination of isovolemic hemodilution, ocular massage, topical beta-blocker and intravenous acetazolamide and anticoagulation with heparin and acetylsalicylic acid) and IAT (maximum of 50 mg tPA). In the IAT group, 24 of 40 (57.1%) patients showed a clinically significant visual improvement of $0.3 logMAR, but these results were not superior to those of the conservative group. A post hoc analysis with time from occlusion to treatment within 12 hours of visual loss showed a trend to better vision gain at Month 1 (20.23 logMAR, P = 0.086) (71). No post hoc analysis was performed for patients who received IAT within 6 hours. OverDumitrascu et al: J Neuro-Ophthalmol 2020; 40: 333-345 all, given the lack of specific outcome data on patients who received IAT within 6 hours of visual loss, no conclusion can be drawn in that regard. SUGGESTIONS FOR CENTRAL RETINAL ARTERY OCCLUSION MANAGEMENT A systematic review showed that various "conventional" therapies for CRAO (e.g., sublingual isosorbide dinitrate, systemic pentoxifylline or inhalation of a carbogen, hyperbaric oxygen, ocular massage, globe compression, IV acetazolamide and mannitol, anterior chamber paracentesis, and 341 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Cerebrovascular Disorders methylprednisolone) are no better than placebo (72). Furthermore, a meta-analysis of 8 studies including 419 patients that received ocular massage, anterior chamber paracentesis, and/or hemodilution demonstrated a significantly lower visual recovery rate compared with the natural history control group (P , 0.001), with a number needed to harm of 10 (95% CI, 6.8- 17.4) (9,73). Hence, none of the abovementioned therapies are recommended by the current AAO practice patterns (17). Because of the wide acceptance and proven efficacy of thrombolytic therapy in acute cerebral and myocardial ischemia, combined with the similarity in pathogenesis and comorbidity of CRAO with these 2 systemic conditions, thrombolytic treatment in CRAO is rational and, indeed, has been used for more than 20 years. Although early visual recovery was the main investigated outcome, timely CRA reperfusion may also decrease the risk of ocular neovascularization and neovascular glaucoma (74). A 1996 survey (75) querying patients' preference for the treatment of CRAO showed that 39% of surveyed adults would accept some risk of stroke and 37% would accept some risk even of death to triple the chances of recovering 20/100 VA in one eye when the unaffected eye is sighted. More than 80% of persons would accept these risks if the unaffected eye is not sighted (75). A 2018 national survey (14) showed 53% of programs' willingness to treat at least some patients with systemic thrombolysis, but only 20% of the queried university-associated teaching hospitals had a formal policy, guideline, or white paper to standardize the approach to treatment. Another nationwide inpatient survey (75) showed that IAT was used in urban centers only in 1.9% of CRAO patients, despite no safety concerns. Previous systematic reviews and meta-analyses included studies with significant heterogeneity regarding fibrinolytic agent mechanism of action, timing and dosage of administration, supplementary management, and control group (9,10,18,76,77). A meta-analysis by Schrag et al (9) and a systematic review by Mac Grory et al (76) demonstrated the benefit of early IV thrombolysis for visual recovery but underscored a need for further RCT assessing the role of IV thrombolysis within 4.5 hours from symptom onset vs placebo. A systematic review of IAT studies suggested a role for IAT in patients that present early, particularly if they have monocular vision (77). A pooled meta-analysis of IAT studies similarly showed promising efficacy of IAT and also recommended a RCT to demonstrate benefit and ensure the safety of the intervention (10). A management algorithm for patients presenting with sudden painless monocular visual loss and a suspicion for CRAO was recently proposed (76). A phase III randomized, blind, double dummy, multicenter study assessing the efficacy and safety of IV thrombolysis (alteplase) in patients with acute CRAO (THEIA Study) is currently enrolling in France. Patients between 18 and 80 years old are randomized to either IV alteplase at a dose of 0.9 mg/kg or aspirin 300 mg within 4.5 hours of symptom onset (https:// clinicaltrials.gov/ct2/show/study/NCT03197194). Until this 342 French RCT results are presented to further guide clinical practice, or another RCT is initiated, we propose an algorithm for patients with suspected acute CRAO, following current guidelines in place for AIS (Fig. 1). CENTRAL RETINAL ARTERY OCCLUSION THROMBOLYSIS THROUGH A TELESTROKE ENCOUNTER Telestroke is increasingly used for brain stroke management. It allows IV alteplase eligibility decision making, timely IV alteplase administration, and triaging of AIS patients who may be eligible for transfer to be considered for emergency mechanical thrombectomy (6). Similar to eye stroke code evaluation, teleeye stroke code evaluations must include an ophthalmological assessment. If an ophthalmologist is not available on site for emergent evaluation, an ocular fundus photograph should be obtained using a nonmydriatic fundus camera (78). The telestroke provider should be guided by an eye care provider to confirm the diagnosis of nonarteritic CRAO and exclude other ocular causes of acute visual loss, before remotely recommending IV alteplase administration or transfer to specialized centers for IAT. CONCLUSIONS Given the lack of established treatment for acute CRAO, it is imperative that future studies evaluate the effect of CRA thrombolysis on visual outcomes. As CRAO is an ocular analog of brain AIS, its cogent and effective treatment should target emergent retinal reperfusion. At this time, the same thrombolytic therapies and time window for AIS patients should apply to CRAO patients. Code eye stroke team must include an in person or virtual eye care provider to help establish the correct diagnosis and exclude ocular signs that may prohibit thrombolytic therapy. Future research should focus on developing advanced, feasible, and real-time retinal tissue viability (core vs penumbra) imaging studies to be incorporated into the current timebased thrombolysis decision-making algorithm. In the meantime, we should continue to educate eye care providers, emergency medical services, and patients to facilitate acute CRAO patients reaching EDs and facilities able to administer thrombolysis and provide acute stroke care (16). The recognition of sudden-onset visual changes as stroke-like symptoms prompted the recent upgrade of the FAST algorithm (Face, Arm, Speech, Time) into BE-FAST (adding B for balance and E for Eyes/Vision) and its incorporation into various educational programs (79,80). Akin to cerebral infarction, once eye strokes are suspected, fast action is needed (16). REFERENCES 1. Leavitt JA, Larson TA, Hodge DO, Gullerud RE. The incidence of central retinal artery occlusion in Olmsted County, Minnesota. Am J Ophthalmol. 2011;152:820-823.e822. 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