Treatment of Nonarteritic Acute Central Retinal Artery Occlusion. 10 In total, it is estimated that greater than 90% of patients

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1 REVIEW ARTICLE Treatment of Nonarteritic Acute Central Retinal Artery Occlusion Rahul A. Sharma, MD,* Michael Dattilo, MD, PhD, Nancy J. Newman, MD, and Valerie Biousse, MD Abstract: Central retinal artery occlusion (CRAO) is an event most often caused by an embolus originating in the ipsilateral carotid artery, aortic arch, or heart. CRAO may result from partial or complete occlusion of the central retinal artery (CRA), which acts as the primary blood supply to the inner neurosensory retina, and typically results in profound vision loss and permanent visual disability. No consensus has emerged regarding the optimal treatment of CRAO. All proposed treatments are of questionable efficacy and many have uncertain risk profiles. In certain circumstances, thrombolysis may be attempted as a treatment option; however, the evidence to support broad use of thrombolytics in the treatment of acute CRAO remains elusive. It is known that the risk factors that predispose to other cardiovascular and cerebrovascular events are often present in CRAO. Accordingly, identification of patients at highest risk of stroke and secondary prevention of ischemic events remains the primary focus of management. This review offers a summary of the clinical presentation, diagnosis, and prognosis of CRAO, with an emphasis on treatment options. Key Words: central retinal artery, occlusion, stroke, ischemia, thrombolysis, thrombolytic therapy (Asia-Pac J Ophthalmol 2018;7: ) Central retinal artery occlusion (CRAO) is a relatively uncommon event, with an estimated incidence of approximately 2 per 100,000 individuals. 1,2 Central retinal artery occlusion shows a male predominance and its incidence increases with age. 2 It is the ocular equivalent of a cerebral infarction and results from occlusion of the central retinal artery (CRA) and subsequent infarction of the inner neurosensory retina. Usually, CRAO causes profound, irreversible monocular vision loss 3 and is associated with a high risk of subsequent cerebral infarction and heart disease. It should be considered as a true ocular and life-threatening emergency. From the *Department of Ophthalmology, The University of Ottawa, Ottawa, ON, Canada; and Departments of Ophthalmology, Neurology, and Neurological Surgery, Emory University School of Medicine, Atlanta, GA. Received for publication March 2, 2018; accepted April 9, V.B. and N.J.N. are consultants for GenSight Biologics. N.J.N. is a consultant for Santhera Pharmaceuticals. V.B. and N.J.N. are supported in part by an unrestricted departmental grant (Department of Ophthalmology) from Research to Prevent Blindness Inc, New York; by NIH/NEI core grant P30-EY06360 (Department of Ophthalmology, Emory University School of Medicine); and by NIH/NINDS (RO1NSO89694). M.D. is supported by the NEI sponsored teaching grant T32-EY (Department of Ophthalmology). The authors have no other funding or conflicts of interest to declare. Reprints: Valerie Biousse, Emory Eye Center, 1365B Clifton Rd, Atlanta, GA E mail: vbiouss@emory.edu. Copyright 2018 by Asia Pacific Academy of Ophthalmology ISSN: DOI: /APO Asia-Pacific Journal of Ophthalmology Volume 7, Number 4, July/August 2018 ETIOLOGIC CLASSIFICATION The CRA originates from the ophthalmic artery, a branch of the internal carotid artery. Central retinal artery occlusion is caused by any process that creates a transient or permanent interruption in the blood supply to the CRA and its causes are similar to those of cerebral infarctions in the anterior circulation. A CRAO may be broadly classified as arteritic or nonarteritic, depending on its etiology. Arteritic CRAO Arteritic CRAO occurs rarely and is a consequence of systemic vasculitis. It is almost always a result of giant cell arteritis (GCA) and is seen in 5 14% of patients with GCA-related vision loss. 4 Although patients with arteritic CRAO often have systemic symptoms and signs of GCA, arteritic CRAO may be isolated and must be considered in all CRAO patients older than 50 years of age in whom no retinal emboli are observed acutely on funduscopic examination. Blood tests looking for a biologic inflammatory syndrome (complete blood count, platelets, erythrocyte sedimentation rate, and C-reactive protein) must be obtained urgently in all these patients. Nonarteritic CRAO In almost all other patients, CRAO is said to be nonarteritic (ie, not related to vasculitis). The most common cause of CRAO is from thromboembolic disease originating in the ipsilateral carotid artery, aortic arch, or heart, although the source of the causative embolus remains unknown in 60% of patients with CRAO. 5 Retinal emboli may be composed of cholesterol (75% of cases), platelet-fibrin (15%), or calcium (10%). Nonfibrinous plaques may develop secondary platelet thrombi. Emboli most commonly lodge at the narrowest portion of the CRA, 6 where the artery transits through the dura of the optic nerve. Central retinal artery occlusion may also occur from occlusion of the CRA immediately posterior to the lamina cribosa. 7 Nonarteritic CRAO represents the ocular analog to ischemic events of the cardiovascular and cerebrovascular systems. 8 As is the case with these entities, CRAO is strongly related to the presence of cardiovascular risk factors, including hypertension, atherosclerosis, and diabetes mellitus. 9 The European Assessment Group for Lysis in the Eye (EAGLE) trial identified greater than 70% stenosis of the carotid artery in 40% of patients with CRAO; 73% had arterial hypertension, 22% had coronary artery disease, 20% had a cardiac arrhythmia, and 17% had valvular heart disease. 10 In total, it is estimated that greater than 90% of patients with CRAO have identifiable cardiovascular risk factors (obesity, smoking, hyperlipidemia, coronary artery disease, or other cardiac abnormalities). 9 Patients without vascular risk factors should be worked up for hypercoagulability. Rarely, intravascular procedures may result in CRAO by dislodging existing embolic 235

2 Sharma et al Asia-Pacific Journal of Ophthalmology Volume 7, Number 4, July/August 2018 plaques from the carotid artery or heart. 11 Less common causes of CRAO also include ipsilateral extracranial carotid artery dissection, which occurs more often in younger patients, either spontaneously or as a result of trauma or aggressive neck manipulation. 12 These patients commonly present with painful ipsilateral Horner syndrome. 13 Transient Nonarteritic CRAO Occlusion of the central retinal artery may occur transiently, causing a temporary loss of vision in 1 eye, and is the retinal equivalent of a transient ischemic attack (TIA) 8 in the anterior circulation. This may occur due to dislodging of the responsible embolus or due to a decrease in perfusion pressure below a certain threshold in the retinal vasculature. 6 Patients with only a transient occlusion typically have a better prognosis and regain more vision after the event, in a manner correlated with the duration of occlusion. 14 Despite the more favorable visual prognosis, patients with vascular transient monocular vision loss and the absence of permanent retinal ischemia on funduscopic examination must be managed emergently, as they are at high risk for subsequent ischemic events. Patients with a transient CRAO are at an increased risk of sustaining a permanent nonarteritic CRAO and are at an increased likelihood of other ischemic events including cerebral infarction, myocardial infarction, and vascular death. Accordingly, immediate evaluation in a stroke center with complete stroke work-up, including magnetic resonance imaging (MRI) of the brain with diffusion-weighted imaging, should be performed immediately on these patients, even if isolated retinal ischemia is presumed Many healthcare professionals mistakenly consider retinal TIAs benign, with a low risk of subsequent stroke, 20 and many patients are never sent for urgent assessment in an emergency department or for stroke evaluation. 21,22 Other Causes of CRAO In a young patient without atherosclerotic risk factors, nonarteritic occlusions may also occur as a result of numerous other factors, including sickle cell disease, myeloproliferative disease, and the use of illicit drugs (intravenous drugs and cocaine). 23 Iatrogenic causes, including cosmetic facial filler injections 24 and ocular compression during prolonged spinal surgery, 25 have also been described. Central retinal artery occlusion is also associated with certain ocular conditions, including elevated intraocular pressure (in the context of acute glaucoma and external ocular compression 26 ). DIAGNOSIS Central retinal artery occlusion is typically diagnosed via urgent ophthalmic examination in the context of sudden, painless, monocular vision loss. The visual acuity may range from nearnormal, especially in patients with cilioretinal artery sparing, to counting fingers or worse. 27 Commensurate dyschromatopsia is usually seen. A relative afferent pupillary defect is present in the affected eye. Characteristic funduscopic findings are seen on clinical examination but may be difficult to identify very acutely. 28 A visible embolus may be seen in the CRA or more distal branches of the retinal vasculature. Other common features include ischemic whitening of the retina due to retinal edema, retinal arterial attenuation, and box-carring due to slowed, segmental blood flow in retinal arterioles. The inner retina is multilayered throughout the posterior pole, except at the fovea; thus, retinal whitening at the fovea does not occur, and a cherry red spot may be evident due to the visibility of the normal choroidal vasculature. The appearance of the optic nerve is normal. When the entire ophthalmic artery is occluded, there is no cherry red spot and the optic nerve appears edematous. Several diagnostic modalities may be used to facilitate the diagnosis, especially in the acute setting, and to follow clinical changes over time. Intravenous fluorescein angiography (IVFA), optical coherence tomography (OCT), and OCT angiography may be used in diagnosis by identifying areas of delayed or absent retinal perfusion. 29 Intravenous FA can also help to group patients into CRAO subtypes (complete, incomplete, cilioretinal sparing). Optical coherence tomography may be useful for monitoring changes in retinal thickness that occur after CRAO. 30 Transbulbar ultrasound may be used to obtain information regarding etiology and prognosis. It was suggested that the absence of a spot sign, which suggests an embolus without a calcific component, may help to identify patients more likely to benefit from thrombolytic therapy. 31 PROGNOSIS Visual Prognosis Typically, CRAO causes profound, monocular visual acuity and visual field loss and results in associated functional disability. As many as 70 80% of patients have a final visual acuity of counting fingers or worse. 27 However, the extent of initial vision loss, along with the degree of recovery after an occlusion, are variable. Indeed, some patients do experience a partial recovery of vision, depending on the presenting visual acuity and the duration of the visual impairment. The specific incidence of spontaneous improvement after nonarteritic, permanent CRAO is unknown, 32 although estimates are that approximately 20% 27 show some recovery of vision, primarily in the first 7 days after the event. Visual improvement may occur spontaneously or after a therapeutic intervention and correlates with the duration of retinal ischemia. 32,33 In a nonhuman primate model, 14,33 no significant retinal damage occurred for 97 minutes after an induced retinal artery occlusion. After this, a degree of retinal damage, particularly to the ganglion cell and inner nuclear layers, did occur in a manner that was significantly associated with CRAO duration. After a duration of 240 minutes, the extent of infarction was massive and irreversible. Visual prognosis is known to be more favorable for the 15 30% of individuals with a cilioretinal artery that supplies a portion of or the whole fovea. 34 As cilioretinal arteries are derived from the posterior ciliary circulation of the choroid, they are unaffected in CRAO. Thus, in these patients, final visual acuity may be as good as 20/20 with preservation of the central field. In a study of 244 patients with CRAO, 20% of patients with a cilioretinal artery had an acuity of 20/40 or better; conversely, those without a cilioretinal artery had a best corrected visual acuity (BCVA) of counting fingers or worse in 93.2% of cases. Patients with a cilioretinal artery were also more likely to experience some improvement in visual acuity: 47% in those with compared with 16% in those without. 27,35 Ophthalmic Sequelae Patients must also be followed for ocular sequelae that can result from profound retinal ischemia. Most occur as a result of 236

3 Asia-Pacific Journal of Ophthalmology Volume 7, Number 4, July/August 2018 Treatment of CRAO neovascularization and have the capacity to result in further vision loss. Rudkin et al 36 reported the prevalence of neovascularization after CRAO as 18.2%; other estimates are as high as 32%. Neovascularization may appear as quickly as 2 weeks after a CRAO and may lead to tractional retinal detachment, neovascular glaucoma, or intraocular hemorrhage. 36 Risk of Subsequent Ischemic Events In 2013, the American Heart Association and American Stroke Association authored a joint publication that included retinal infarction in the broader definition of central nervous systemic infarction (stroke) and transient retinal infarction within the definition of TIA. 8 This lent further credence to the idea that CRAO patients must be viewed as individuals at high risk for subsequent ischemic events. Between 15 25% of patients with acute retinal ischemia show signs of concurrent cerebral ischemia on diffusion-weighted MRI even when there are no neurological symptoms. Several studies indicate that CRAO is associated with an increased risk of further ischemic events, including cerebral ischemia 37,38 and increased cardiovascular events with high morbidity and mortality. 39 Accordingly, patients with either permanent nonarteritic CRAO or transient symptoms must be evaluated in a similar manner to patients with other cerebral ischemic events. These patients require immediate MRI of the brain with diffusion-weighted imaging, neurologic evaluation, complete stroke work-up looking for a source of emboli, and long-term cardiac monitoring. Secondary risk modification, including smoking cessation and optimization of cardiac risk factors, are essential to reduce morbidity and mortality. 40 Immediate evaluation in an emergency care center with a certified stroke center is recommended. Unfortunately, surveys of comprehensive ophthalmologists 21 along with vitreoretinal specialists and neurologists 22 regarding their practice patterns revealed that only 35% of ophthalmologists referred patients for further work-up after CRAO and only 18% of vitreoretinal specialists pursued a hospital-based work-up for a CRAO that occurred less than 12 hours before the initial evaluation. When they are referred to a stroke center, patients are typically worked up within 24 hours to determine the underlying source of the occlusion and evaluate for cardiovascular risk factors. If the work-up reveals a cause for the CRAO, the patient is admitted to the stroke unit for immediate treatment (for example, urgent carotid endarterectomy if a carotid stenosis is found); if the work-up is negative and the brain MRI is normal, the patient is discharged with secondary prevention measures and follow-up within 2 weeks with a stroke neurologist. Quality of Life Fortunately, CRAO is most often a monocular disorder; thus, the likelihood of significant disability is less than with cerebral arterial occlusions. 41 However, CRAO-associated vision loss has considerable effects on quality of life and is associated with issues of safety and independent living. 42 Patients should be provided with or referred for visual rehabilitation when visual impairment occurs. TREATMENT OF CRAO A number of therapies have been used to treat CRAO. These include so-called conservative therapies, such as carbogen inhalation, intravenous acetazolamide and mannitol therapy, ocular massage, anterior chamber paracentesis, and various vasodilating medications. More aggressive treatment regimens have combined several of these approaches in an attempt to restore retinal blood flow. 43 A number of studies have also proposed the use of thrombolytics with controversial results. 10,44 46 Ultimately, none of the conservative therapeutic interventions have shown a benefit in altering the natural history of CRAO and improving final visual outcome. Therefore, management is primarily geared toward secondary risk modification and the prevention of subsequent ischemic events, including myocardial infarction, stroke, and cardiovascular death. Pharmacologic Treatment Sublingual Isosorbide Dinitrite and Pentoxyphylline Pentoxyphylline is used in the treatment of peripheral vascular disease and improves tissue perfusion by increasing erythrocyte flexibility, reducing blood viscosity, and increasing microcirculatory flow. In a small randomized controlled trial (RCT), 10 patients were assigned to either pentoxyphylline or placebo for 4 weeks. 47 Compared with the controls, patients receiving pentoxyphylline demonstrated an increase in CRA blood flow by duplex scanning, but no visual recovery was demonstrated. Isosorbide dinitrate causes a mild decrease in intraocular pressure along with corresponding dilation of retinal vasculature and increased perfusion in the retinal artery. Like pentoxyphylline, it has not been shown to improve visual outcome in CRAO. 43 Carbogen Carbogen is a mixture of 95% oxygen and 5% carbon dioxide. Inhalation of this mixture (or hyperventilation of plain room air) is thought to increase carbon dioxide blood concentration and create respiratory acidosis. This prevents oxygen-induced vasoconstriction, allowing maintained or improved blood flow to the retinal tissue, 48 but no significant visual recovery has been seen using this treatment. 49 Hyperbaric Oxygen Hyperbaric oxygen is used infrequently in acute CRAO to increase oxygen tension and oxygen delivery to ischemic retinal tissue. 50,51 It is used primarily as a temporizing measure, until other therapies are attempted or spontaneous reperfusion occurs. 3 Two large retrospective case series have suggested some initial visual improvement from this therapy, 52,53 although one lacked a control group 53 and the other showed that outcomes in treated and untreated patients were similar after 3 months. 52 Other Interventions Intravenous acetazolamide, intravenous mannitol, and topical ocular antihypertensives may be used to decrease intraocular pressure and increase retinal perfusion pressure; however, no reliable data exist to support improved visual outcomes after their use. 43 Nonpharmacologic Interventions Ocular Massage Ocular massage involves compression of the globe with a 237

4 Sharma et al Asia-Pacific Journal of Ophthalmology Volume 7, Number 4, July/August 2018 contact lens or digital pressure; it may be used in conjunction with acetazolamide in patients with a visible arterial embolus. Massage causes retinal arterial dilatation and, presumably, the combination with acetazolamide creates large fluctuations in intraocular pressure that are thought to mechanically dislodge the embolus into the more peripheral retinal circulation. 54 Anterior Chamber Paracentesis Withdrawal of a small volume (0.1 to 0.2 ml) of aqueous fluid from the anterior chamber causes a decrease in intraocular pressure and is reported to induce dilatation of the retinal arteries that occurs from deformation of the globe. 29 However, a large case series has indicated that few patients benefit from this therapy. 32 Nd:YAG Laser Embolectomy A recent meta-analysis 55 describes all 61 cases (including CRAO and branch retinal artery occlusion) in which neodymiumdoped yttrium aluminum garnet (Nd:YAG) laser has been used to dislodge the embolus. This technique was first described in 2004 as a single case report. 56 Significant complications, including vitreous hemorrhage and the creation of false aneurysms, have prevented further research and impeded any certain conclusions regarding this therapy. Pars Plana Vitrectomy Pars plana vitrectomy followed by surgical removal of the embolus has been attempted in case studies and small case series, 57 but evidence to support its use remains limited. THROMBOLYSIS FOR TREATMENT OF CRAO Overview Urokinase, streptokinase, and tissue plasminogen activator (tpa) are thrombolytics, which all act as fibrinolytic agents, and whose binding induces a conformational change of a thrombus that promotes the conversion of plasminogen to plasmin and results in clot lysis. 58,59 Thrombolytics are used in the treatment of acute cerebral infarction and, as CRAO is viewed as an ocular analog to these other ischemic phenomena, may represent a plausible treatment option for acute CRAO. As with any stroke, the interval between the event and intervention time is critical in CRAO. The debate continues regarding the ideal therapeutic window. Primate studies suggest that therapy is most effective in preventing permanent retinal ischemia when given less than 3 hours after the onset of symptoms. 14 Certain investigators have argued that a longer window, up to 6 12 hours, may still be beneficial. 60 For thrombolytics, some have proposed a 4.5-hour treatment window based on strong evidence supporting thrombolysis within this time period in ischemic stroke. 61 However, in the largest clinical trial evaluating thrombolytics for CRAO, therapy was administered within 24 hours of the onset of symptoms. 10 The use of thrombolytics for acute CRAO is hindered by several limitations. First, for a patient with undifferentiated monocular vision loss, initial assessment by an eye care practitioner is critical, creating a delay in initiating treatment for CRAO. 41 Second, there is no established treatment protocol for the use of thrombolytics in the treatment of CRAO. Instead, most practitioners rely on established stroke protocols to guide management Third, there is a paucity of reliable data to indicate the efficacy of thrombolytics in the treatment of CRAO. The current studies, including RCTs, have provided conflicting evidence regarding the efficacy and safety of thrombolytics. Physicians must carefully interpret the data while weighing the risks of therapy and the circumstances of the individual patient. Fibrinolysis may be delivered either intravenously (IVT) or intra-arterially (IAT) (via direct catheterization of the ophthalmic artery) and both routes have been used to treat acute CRAO. Although the therapeutic window and general contraindications for either route are the same, each comes with certain advantages and disadvantages. Traditionally, IVT is thought to offer more rapid and easier administration of tpa, although it does subject the patient to an increased risk of systemic hemorrhage. Conversely, IAT is thought to prolong the treatment window and offers the ability to offer a smaller dose locally to the occluding clot. 62 Intraarterial thrombolytics also create potential complications related to catheter manipulation of the intracranial arteries. 62 Clinical Use The application of thrombolysis stroke protocols to CRAO patients has been met with some criticism. Thrombolytics are restricted only to stroke patients meeting strict eligibility criteria to minimize the risk of hemorrhagic complications. These criteria exclude patients with a head injury or stroke in the past 3 months, major surgery within the past 2 weeks, any history of intracranial hemorrhage, systolic blood pressure greater than 185 or diastolic greater than 110, rapidly improving symptoms, seizure at stroke onset, concomitant use of anticoagulants or a tendency for poor coagulation, or an abnormally high or low blood glucose. 60,61 Instituting rapid thrombolysis for CRAO also has several practical limitations. Patients rarely present soon enough to gain maximal benefit from therapy. Due to the monocular nature of symptoms, many patients mistakenly presume a benign etiology and may wait for spontaneous resolution; others that experience vision loss during sleep have an unavoidable delay in seeking care. 41 On average, the percentage of patients in whom tpa is attempted greater than 8 hours after the onset of symptoms approaches 50%. 62 In the EAGLE study, treatment time in the IAT group was on average close to 13 hours after the onset of symptoms. 10 In addition, to offer IAT and provide timely administration, 24-hour access to IVFA and interventional radiology services is required. 63 Efficacy Both IVT and IAT after CRAO have been used with variable success. In 2015, a meta-analysis of IVT for CRAO published by Schrag et al 64 included 147 total patients and suggested that IVT was beneficial when administered within 4.5 hours of symptom onset and that it resulted in improved visual outcomes when compared with patients receiving no therapy. However, other studies have provided conflicting results. An Australian phase 2 RCT by Chen et al 44 enrolled 16 patients and evaluated the use of IVT for patients with CRAO and less than 24 hours of symptoms; it found no difference in visual outcomes between treatment and control groups at any follow-up duration. The literature on IAT also provides conflicting recommendations regarding its efficacy. Several cases 65 and case series 60,66 have supported the use of IAT, suggesting that treatment may improve final visual acuity while causing few serious complications. Aldrich et al 67 conducted a single-center nonrandomized

5 Asia-Pacific Journal of Ophthalmology Volume 7, Number 4, July/August 2018 Treatment of CRAO retrospective interventional study of 42 consecutive patients treated within 15 hours of symptom onset. The study compared 21 patients receiving local IAT along with conservative therapy with 21 receiving conservative measures alone. Multivariate logistic regression for several potential confounders indicated that patients receiving IAT were 36 times more likely to experience visual improvement and 13 times more likely to experience an improvement of 3 lines or more. 67 In 2005, a Swiss group (Arnold et al 68 ) published a retrospective case-control study of 37 patients with acute monocular blindness secondary to CRAO that were treated with IAT using urokinase within 6 hours of the onset of symptoms. Vision, when compared with a group of 19 control patients, was more likely to improve in patients treated with IAT. Younger patients, along with those treated within 4 hours, showed a trend for better visual outcomes. 68 However, this study has certain limitations: the extent of visual field loss was not included as an outcome measure 41 and the number of patients enrolled was small. A study of 101 CRAO patients treated with either IAT (n = 57) or standard treatment (n = 44) via retrospective review indicated no significant difference in final visual acuity between the 2 groups for patients experiencing total or subtotal CRAO, although early reperfusion was greater in the IAT group. 45 A prospective randomized multicenter clinical trial, the EAGLE trial, compared treatment outcomes in 84 patients treated with conservative measures (n = 40) and IAT (n = 44). 10 Patients in both arms were treated with 5 days of intravenous heparin in addition to IAT or conservative therapy. Heparin had not been used in previous trials and this may have affected the outcome of the trial. 70 The EAGLE study was the first to compare the benefit of IAT with conservative therapies in patients with CRAO. The study enrolled adult patients with symptoms for less than 20 hours and the mean interval between first symptoms and therapy was approximately 11 hours; the mean BCVA improved significantly in both groups (57% in treatment and 60% in control arm) but did not differ between groups. Based on these results, the investigators concluded that they could not recommend IAT for the treatment of CRAO. 10 However, some have argued that the number of participants was too low to draw definite conclusions regarding risks and benefits and that the treatment window was too long. 62 A larger, multicenter clinical trial has been suggested to better study the safety and efficacy of this treatment. Risk Profile Potential adverse effects of therapeutic IAT include local site hemorrhage, intraretinal and intracerebral hemorrhage, and TIAs. The most feared complication of any thrombolytic treatment is symptomatic intracerebral hemorrhage (SIH). Adverse events are thought to occur more commonly in the elderly (older than 80 years of age) and those with significant cardiovascular risk factors. 71 Among patients with minor stroke scores (National Institutes of Health Stroke Scale, NIHSS), the estimated risk of SIH should be approximately 2%, based on a pooled analysis including only patients with minor strokes (NIHSS 0 5). 72 However, in the EAGLE study, 4% of patients experienced SIH (37.1% of patients experienced adverse reactions overall) after IAT and 37% had more minor reactions; the study was terminated early due to these adverse events. 10 In the study by Chen et al 44 examining the use of IVT in CRAO patients, the rate of SIH was 12.5%. The complication rate of both trials is of concern, despite the lower rate in the more recent EAGLE trial. Ultimately, the difficulty defining an acceptable risk profile must include patient preference. A 1996 study of adults with normal vision indicated that 39% and 37% of those surveyed would accept some risk of stroke and death, respectively, to triple their chances of recovering 20/100 visual acuity in 1 eye while binocular. More than 80% of individuals surveyed would tolerate the risk if they were monocular. 73 CURRENT PRACTICE PATTERNS Given the conflicting evidence on its efficacy, most practitioners remain hesitant to recommend the use of thrombolytics in CRAO. 41 A survey of 1595 physicians in the United States, including 350 neuro-ophthalmologists registered with the North American Neuro-Ophthalmology Society, detailed the management of 258 patients with CRAO seen within 12 hours of initial vision loss. 21 Although the majority of physicians continue to attempt conservative treatment options, thrombolytics were attempted by only 23% of surveyed physicians and 16% of neuro-ophthalmologists. Another survey of 448 physicians indicates that most neurologists pursue a hospital-based evaluation, whereas most retinal specialists pursue an outpatient work-up. 22 CONCLUSIONS: FUTURE USE OF THROMBOLYTICS IN CRAO Although uncommon, CRAO is a devastating event that most often results in profound, irreversible monocular vision loss and considerable functional limitation. Given the shared pathophysiology of CRAO and other systemic ischemic events, there is continued optimism regarding the role of thrombolytic agents in the treatment of this condition. However, reliable evidence to support the broad use of thrombolytics in the treatment of acute CRAO remains elusive. The available evidence is conflicting; the largest RCT assessing the use of IAT in CRAO patients provides no evidence to support its use and indicates a significant rate of adverse events, whereas other reports support a visual benefit for patients receiving both IAT and IVT. 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