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Show STATE OF THE ART Thrombolysis for Central Retinal Artery Occlusion Valerie Biousse, MD, Olivier Calvetti, MD, Beau B. Bruce, MD, and Nancy J. Newman, MD Abstract: Central retinal artery occlusion ( CRAO) frequently causes severe and irreversible visual loss. For many years, various conservative treatments have been proposed for acute CRAO, but their efficacy remains unproven. Over the past 20 years, CRAO has also been treated with thrombolytic agents administered intravenously or intra- arterially However, all thrombolytic studies are retrospective and uncontrolled, so that the benefit of this treatment remains uncertain. A prospective controlled clinical trial is ongoing in Europe and should provide more reliable information. Even if this trial demonstrates a benefit, thrombolytic treatment is unlikely to become widespread in the management of CRAO unless it can be deployed quickly after the event. (/ Neuro- Ophthalmol 2007; 27: 215- 230) Central retinal artery occlusion ( CRAO) typically causes severe and permanent visual loss in the affected eye ( 1- 7). Even if visual acuity spontaneously improves in up to 22% of patients with nonarteritic CRAO ( 4), less than 10% of patients report a meaningful recovery of vision ( 7,8). To date, none of the " conservative" treatments classically offered to patients with acute CRAO has proven effective ( Table 1). Furthermore, these treatments have not been evaluated in randomized clinical trials, and their presumed efficacy is based entirely on small retrospective case series or personal experience ( 7- 27). With the now accepted use of thrombolysis for acute cerebral infarctions ( 28), it is logical to consider the use of such agents in the treatment of CRAO. A few centers ( mostly from Germany and Switzerland) have used Departments of Ophthalmology ( VB, OC, BBB, NJN), Neurology ( VB, NJN), and Neurological Surgery ( NJN), Emory University, Atlanta, Georgia. This study was supported in part by a departmental grant ( Department of Ophthalmology) from Research to Prevent Blindness, Inc, New York, NY, and by core grants P30- EY06360 ( Department of Ophthalmology) from the National Institutes of Health, Bethesda, MD. Dr. Newman is a recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award. Address correspondence to Valerie Biousse, MD, Neuro- ophthalmology Unit, Emory Eye Center, 1365- B Clifton Road, NE, Atlanta, Georgia 30322; E- mail: vbiouss@ emory. edu intravenous ( IV) or intra- arterial ( IA) thrombolysis to treat patients with acute CRAO ( 29- 61). Although some studies have suggested that thrombolysis may improve the visual outcome of CRAO, this treatment remains controversial ( 51,62- 64). A multicenter, randomized European clinical trial is ongoing [ European Assessment Group for Lysis in the Eye ( EAGLE)] ( 65). However, it is still unclear how its results will practically affect the treatment of CRAO, a diagnosis only rarely made within a few hours of acute visual loss. We have summarized the evidence relating to whether CRAO should be managed like another ischemic stroke, whether any of the conservative treatments are helpful, and whether thrombolysis is the appropriate treatment of acute CRAO. METHODS English and non- English language articles were retrieved using a keyword search of Medline. Search terms included " central retinal artery occlusion," " thrombolysis," and " fibrinolysis." This search was supplemented by manually searching the reference lists of all articles. All reports of thrombolysis in CRAO were included. Cases of branch retinal artery occlusions ( BRAOs) were excluded. Although many of these articles were case reports and 19 articles were not written in English, all were included in our review. Articles were translated from French, German, Japanese, Chinese, Spanish, and Italian. As an exception, only the abstract in English was reviewed for one article in Czech ( 39). Information on study design, outcome, and analyses was documented in a standardized data extraction form. Information entered included 1) year of publication, 2) country of origin, 3) number of patients treated, 4) study design, 5) modalities of thrombolytic treatment [ IV or intraarterial with selective catheterization of the internal carotid artery ( ICA) and its branches, type and dose of thrombolytic agent used], 6) delay between onset of CRAO and thrombolysis, 7) visual outcome, and 8) complications. Two investigators ( VB and OC) reviewed the articles independently. A total of 35 articles ( including a meta- analysis published in 2000) ( 51) were included in this review. Other review articles and meeting abstracts were not included. J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 215 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Biousse et al TABLE 1. " Conservative" treatments proposed for the treatment of acute central retinal artery occlusion Goal Proposed treatment Dislodge an embolus from the central retinal artery Reduce intraocular pressure and increase retinal blood flow Vasodilation of ocular blood supply Improve retinal circulation Reduce retinal edema Maintain retinal oxygenation until spontaneous reperfusion Act on the thrombus Ocular massage Nd: YAG laser ( 0.5- 1.0 mJ) ( attempt to lyse the embolus)* Surgical removal of clot from the central retinal artery ( vitrectomy, vessel cannulation, and thrombus disruption)* Ocular massage Anterior chamber paracentesis Topical glaucoma medications Acetazolamide ( 250- 500 mg IV) Mannitol ( IV) Glycerol ( PO) Calcium channel blockers ( PO or IV) Prostaglandin El ( IV) ( potent vasodilator of the microcirculation or capillary system used to treat patients with peripheral vascular disease) Sublingual nitroglycerin ( rapid acting vasodilator used for acute coronary syndromes) Retrobulbar injection of papaverine ( vasodilator, inhibitor of phosphodiesterase) or tolazoline ( vasorelaxant, nonselective adrenoreceptor blocker) Lidocaine hydrochloride Acetylcholine Atropine Inhalation of 02/ C02 Rebreathing bag Pentoxifyllin ( oral agent used in systemic vascular diseases to improve perfusion of occluded vessels by increasing red blood cell deformability, reducing blood viscosity, and decreasing the potential for platelet aggregation and thrombus formation) Hemodilution ( based on the observation that reducing hematocrit levels lowers plasma viscosity, which may lead to improved retinal circulation and perfusion) Methylprednisolone IV Hyperbaric oxygen Anticoagulants ( heparin IV acutely) Antiplatelet agents IV, intravenous; PO, oral. * Although YAG laser and surgery are invasive treatment modalities, we kept them in this table because they were considered by previous authors to be " conservative treatments," and they differ from thrombolysis. The main outcome reported in these studies was improvement in visual acuity from baseline at the completion of the follow- up period. Other outcomes reported in some studies were improvement of the visual field from baseline at the completion of the follow- up period, and evidence of revascularization of retinal arteries on retinal fluorescein angiograms performed before and after thrombolysis. Because only a few studies reported results of visual field tests and fluorescein retinal angiograms and because reperfusion of the central artery on a fluorescein angiogram is meaningless if not accompanied by measures of visual function, we recorded visual acuity as the primary indicator of outcome. We specifically noted when the authors mentioned a " complete visual recovery" or major improvement in visual acuity from baseline to after thrombolytic administration, arbitrarily categorized into " improved visual acuity by at least 8 Snellen lines or 4 Snellen lines." For each study for which data were available, the pretreatment visual acuity, post- treatment visual acuity, and treatment delay were recorded. Visual acuity data were converted to logMAR units, and a difference between post-and pretreatment acuity was calculated. Linear regression 216 © 2007 Lippincott Williams & Wilkins Central Retinal Artery Occlusion J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 analysis of the relationship between the difference in acuity and treatment delay was performed. IS CRAO LIKE ANY OTHER STROKE? CRAO leads to irreversible retinal infarction if the retinal blood flow is not restored rapidly. The diagnosis is easily made clinically in a patient presenting with acute visual loss, an ipsilateral relative afferent pupillary defect, retinal edema with attenuation of the retinal arteries, and a cherry red spot ( Figs. 1- 3). Visual acuity at the initial prezsentation is usually very poor, with 90% of patients having no better than finger counting vision ( 3). A classification of CRAO in 3 stages is based on the severity of visual acuity loss at presentation and on fundus appearance ( Table 2). This classification is useful for the prognosis of acute CRAO ( 4,53,66). Approximately one- third of human eyes have a patent cilioretinal artery that may allow for preserved central visual acuity when the cilioretinal artery supplies the foveal region in patients with CRAO ( 4,67- 69). Retinal arterial emboli are seen in up to 20%- 40% of patients with acute CRAO ( 2,3) and are believed to originate mostly from the ICA, although all causes of cerebral infarction have also been reported to cause CRAO. The natural history of CRAO remains a subject of debate. The largest series evaluating the outcome of CRAO included 171 eyes with nonarteritic CRAO and no cilioretinal artery sparing ( 4). It showed that 22% of patients who initially presented with visual acuity of count fingers had improved visual acuity at follow- up. Other authors have suggested that between 14% ( 7) and 35% ( 5) of patients with CRAO improve with conservative treatments. Rare patients with spontaneous complete recovery have also been reported ( 70). The central retinal artery is a branch of the ophthalmic artery, which arises from the intracranial ICA. Hence, an ocular infarction from central retinal or ophthalmic artery occlusion is appropriately considered an infarction in the anterior circulation territory. This concept is well illustrated by data accumulated on the risk of ipsilateral cerebral infarction after an episode of transient retinal ischemia ( transient monocular visual loss or retinal transient ischemic attack [ TIA]) ( 71). The North American Symptomatic Carotid Endarterectomy Trial ( NASCET) has shown this stroke risk to be approximately 10% after 3 years for patients with ipsilateral atheromatous carotid artery stenosis ( 72,73). However, the same study also showed that the risk of cerebral infarction after a retinal TIA is much lower than that after a hemispheric TIA ( 73). This NASCET finding is probably related to the anatomy of the ophthalmic artery, which branches off the ICA at an angle of 90°. Why would emboli take a 90° turn instead of simply flowing distally into one of the intracranial branches of the ICA? Interestingly, two studies ( 74,75) showed that retinal ischemia is caused more often by carotid stenosis than by a cardiac source of emboli. The authors explained this observation by rheologic phenomena in which very small emboli from carotid stenosis tend to stick to the carotid wall and may therefore be more likely to make a 90° turn if they happen to flow by the ophthalmic artery origin, whereas larger emboli originating in the heart are localized in the center of the flowing blood and have a tendency to be pushed more distally into the intracranial circulation ( 74). The risk of CRAO after a retinal TIA is not reliably known; it is estimated to be only 1% per year ( 76). Therefore, although there is no doubt that CRAO is an ischemic stroke in the anterior circulation, it seems to differ from most cerebral infarctions. CRAO also differs from other stroke in being far less common. Non- CRAO stroke is the third leading cause of death and one of the leading causes of disability in North America, Europe, and Asia. Stroke costs now exceed $ 45 billion per year. These numbers justify the numerous randomized stroke trials and the recommendations for aggressive secondary stroke prevention. On the other hand the annual incidence of CRAO is only about 0.85 per 100,000 ( 25). In addition, the mortality of acute CRAO is minimal, with a morbidity based mostly on whether affected patients have a normally sighted fellow eye. Therefore, unless CRAO occurs in the only sighted eye, the cost of CRAO cannot be considered equivalent to the cost of stroke in general. HOW SHOULD CRAO BE MANAGED? Should Patients With CRAO be Admitted Immediately for Observation and Workup? Patients with sudden monocular visual loss rarely present to the emergency room acutely. In most cases, they are evaluated by a community optometrist, ophthalmologist, or primary care physician and subsequently are referred to a specialist who will make the diagnosis. With this delay in diagnosis, it is too late for any effective treatment. Natural history data suggest that in cerebral infarctions and cerebral TIAs, the risk of recurrent infarction is highest within the first few days after the first ischemic event. Given that patients with CRAO typically present to physicians several days after the event, it is reasonable to recommend that the etiologic workup be obtained promptly but on an outpatient basis. This workup is often best facilitated by the primary care physician, who can also immediately begin treatment for secondary prevention of cerebral infarction and cardiovascular disease. The only real emergency in this setting is to rule out giant cell arteritis in patients older than 50 years. 217 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Biousse et al TABLE 2. Classification of central retinal artery occlusion Stage 1: Incomplete CRAO Figure 1: Stage 1 CRAO Decreased visual acuity Mild retinal edema Stage 2: Subtotal CRAO Figure 2: Stage 2 CRAO Severely decreased visual acuity Marked retinal edema Cherry red spot Stage 3: Total CRAO Figure 3: Stage 3 CRAO* Vision reduced to no light perception Massive retinal edema Cherry red spot may be absent CRAO, central retinal artery occlusion. Adapted from Schmidt and Schumacher ( 66) and from Hayreh and Zimmerman ( 4). * The presence of cilioretinal artery sparing, shown in Figure 3, should be noted in all cases. 218 © 2007 Lippincott Williams & Wilkins Central Retinal Artery Occlusion J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 On rare occasions, a patient with CRAO will be evaluated within a few hours of visual loss. In theory, these patients have the highest risk of recurrent ischemia and cerebral infarction and may be good candidates for acute treatment of retinal infarction. They should be admitted for observation, treatment, and immediate workup. Patients younger than 50 years, in whom a CRAO is extremely unusual and often points to an underlying systemic vascular disorder, should be admitted for observation and workup even if their presentation is delayed. Indeed, the likelihood of discovering an ICA dissection, a systemic vasculopathy, a cardiac abnormality, or a coagulopathy is very high in the young patient with acute CRAO. Should the Workup for CRAO be Similar to That for Other Stroke? Patients older than 50 years presenting with an acute or subacute CRAO need to be evaluated on an emergency basis for giant cell arteritis. Once giant cell arteritis is ruled out, it is appropriate to obtain the same workup as for patients with a cerebral infarction. The caveat is that ipsilateral ICA disease ( atheroma or dissection) is by far the most common identified cause of CRAO, whereas cardiac causes are much less common. Nevertheless, all causes of cerebral infarction have been reported to cause CRAO, and a stepwise approach that involves evaluating the most common causes first is recommended ( Table 3). What are the Indications for Conservative Therapy for CRAO? Since the first description of CRAO by von Graefe in 1859 ( 77), various treatments have been advocated ( Table 1). Most recommendations are based on very small series or personal experience, and none has been evaluated in a controlled clinical trial ( 7- 27). Most ophthalmologists agree that attempting to dislodge a visible retinal embolus by ocular massage and nonaggressive decrease of intraocular pressure by medications may be useful in some patients. However, there is no evidence supporting the use of anterior chamber paracentesis, vasodilators, hemodilu-tion, hyperbaric oxygen, or surgical removal of the embolus ( 8,11). Corticosteroids should only be used when arteritic CRAO ( from giant cell arteritis) is suspected. Anticoagulants should be reserved for the secondary prevention of cerebral or ocular infarction in those rare patients who have an underlying disease requiring long- term anticoagulation therapy such as atrial fibrillation, acute ICA dissection, or selected hypercoagulable states such as antiphospholipid antibody syndrome. TABLE 3. Causes and evaluation of patients with acute central retinal artery occlusion* Causes Tests Giant cell arteritis Carotid disease Atheroma Dissection Fibromuscular dysplasia Vasculitis Tumor Occlusion by thrombus or cardiac embolus Aortic arch atheroma Cardiac source of emboli Hypercoagulable disorder CBC, platelets, ESR, CRP Consider fluorescein angiogram Temporal artery biopsy if high suspicion Carotid ultrasound ( with transcranial Doppler evaluating ophthalmic artery and intracranial circulation) CT angiogram or MRA of head and neck Transthoracic ± transesophageal echocardiogram CT- angiogram of the aortic arch or MRA of the aortic arch Electrocardiogram Transthoracic ± transesophageal echocardiogram Holter monitoring if indicated Blood tests looking for hypercoagulable states and causes of hyperviscosity, including thrombophilia, antiphospholipid antibodies, hyperhomocysteinemia, sickle cell disease, monoclonal gammopathy, cancer, infection, disseminated intravascular coagulation ( 84) CBC, complete blood count; CRAO, cerebral retinal artery occlusion; CRP, C- reactive protein; ESR, erythrocyte sedimentation rate. * This work- up is proposed as a general guideline. It needs to be adapted to the patient's age and risk factors, and clinical symptoms and signs. It also varies from one institution to another. The causes of acute CRAO and appropriate tests are organized from the most urgent or common to the least likely. 219 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Biousse et al TABLE 4. Previously published studies on the treatment of central retinal artery occlusion with intravenous thrombolysis Authors, year, country Rossman, 1966, Germany Lohse and Weller, 30 1969, Germany Coscas et al, 1969, France Sautter and Rossmann, 1971, Germany Guadalupi et al, 33 1981, Italy Annonier et al, 35* 1988, France Bertram et al, 7 1991, Germany Mames et al, 42 1995, USA Barfh et al, 45 1996, Germany Rumelt et al, 25 1999, Israel Kattah et al, 54 2002, USA Von Mach et al, 57 2005, Germany Yao et al, 59* 2005, China Patients ( age, range, in years) 10 ( 39- 85) 8 ( 46- 74) 1( 45) 23 ( 31- 85) 2 ( 56, 43) 5 ( 25- 67) t 2 ( 29, 59) 3 ( 56- 74) 2 ( 56, 75) 11 ( 47- 80) 12 19 ( mean age 63) 13 ( 38- 72) Type of study Retrospective Retrospective Case report Retrospective Case reports Retrospective Case reports Retrospective Retrospective Retrospective systematic treatment and evaluation Prospective Retrospective Retrospective AC, anterior chamber; CRAO, central retinal artery occlusion; IA, intra- arterial; Treatment Conservative treatment NA NA Retrobulbar injection of vasodilators, IV papaverine, heparin NA Hemodilution None Pentoxifyllin, Aspirin Ocular massage, AC paracentesis, rebreathing bag, SL nitroglycerin, topical medication to lower IOP NA Ocular massage, SL isosorbide trinitrate, IV acetazolamide, IV mannitol, 500 mg IV methylprednisolone, retrobulbar tolazoline Anterior chamber paracentesis if IOP > 12 None None protocol Thrombolysis IV streptokinase IV streptokinase IV streptokinase, corti steroids IV streptokinase IV urokinase, heparin IA urokinase ( 2 pts) IV urokinase ( 2 pts) IV streptokinase ( 1 pt) IV t- PA, heparin IV rt- PA ( 2 pts) IV streptokinase ( 1 pt), heparin, warfarin, aspirin IV ( 1 pt) IV t- PA ( 1 pt) heparin IV streptokinase IV t- PA, heparin, warfarin Systemic urokinase IA urokinase ( 6 pts), IV urokinase ( 7 pts) IOP, intraocular pressure; IV, intravenous; NA, not available; In most studies, the investigators monitored the fundus and the ophthalmic artery perfusion during the infusion of thrombolysis. Thrombolysis * Studies also using intra- arterial thrombolysis. fThe patients published by Annonier et al in 1984 ( 24) are also included in the article published by the same i mthor in 1988 ( 35). How Would Thrombolysis be Performed for Acute CRAO? In CRAO, as in cerebral infarction, thrombolytic agents can be administered intravenously or intra- arterially ( into the ICA or selectively into the ophthalmic artery) ( Tables 4 and 5) ( 1). IV thrombolytics are easy to administer even by nonspecialized physicians in the emergency room. The workup required before treatment is minimal and includes blood tests and a brain CT scan to rule out cerebral hemorrhage or a large cerebral infarction, which are contraindications to thrombolysis. IV streptokinase was administered to a few patients with CRAO or BRAOs beginning in the late 1960s ( 25,29- 32,35,36,45) and was subsequently replaced by urokinase ( 35,57,59) and t- PA ( 37,42,45,54), which are better tolerated ( Table 4). However, IV administration of thrombolytics increases the risk of systemic as well as cerebral hemorrhage ( Table 6) ( 28). To decrease the risk of complications, very strict guidelines were proposed for the treatment of cerebral infarction with resultant hesitation in using such a " dangerous" treatment. Despite the success of the 1995 National 220 © 2007 Lippincott Williams & Wilkins Central Retinal Artery Occlusion J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Delay in thrombolysis 5 hours- 10 days 5 hours- 8 days 15 hours 3 h- 10 days 4 h- 7 days 3- 11 hours < 7 hours 2.75- 5.5 hours NA 1- 48 hours < 24 hours 1- 48 hours ( median 5.5) 5- 38 hours PO, oral; pt, patient; rt- PA, Results 1/ 10 pts had normal VA, 4 pts had improved VA > 4 Snellen lines 3/ 8 pts improved VA > 4 Snellen lines Temporary improvement with VA 20/ 20; recurrent visual loss when streptokinase was discontinued 5/ 23 pts had improved VA > 8 Snellen lines, 4/ 23 pts had improved VA > 4 Snellen lines 2/ 2 pts had improved VA > 8 Snellen lines 4/ 5 pts had improved VA > 4 Snellen lines 1/ 2 pts had improved VA > 8 Snellen lines 2/ 3 had improved VA > 8 Snellen lines, 1/ 3 pts had improved VA > 4 Snellen lines No improvement in VA 8/ 11 pts had improved VA > 5 Snellen lines 10/ 12 pts had improved VA, 4/ 10 pts had improved VA > 8 Snellen lines 11/ 19 pts had improved VA > 4 Snellen lines IA group: 3/ 6 pts had improved VA by > 4 Snellen lines; 2/ 6 pts had improved VA by > 2 lines; IV group: 1/ 7 pts had improved VA by 2 lines recombinant t- PA; SL, sublingual; VA, visual acuity. was usually discontinued when reperfusion of retinal arteries or the ophthalmic artery was seen Complications of fibrinolysis 1/ 11 pts had a fatal cerebral hemorrhage 1/ 8 pts had a mediastinal hemorrhage None 4/ 23 pts with cerebral hemorrhage 1/ 23 pts with shock None None None None 2 pts had cerebral hemorrhage ( 1 death, 1 disabled) None None 4/ 19 pts with hemorrhagic complications None on funduscopic examination or on the angiogram. Institute of Neurological Disorders and Stroke ( NINDS) study using IV t- PA within 3 hours in acute cerebral infarction ( 78) and its subsequent approval by the U. S. Food and Drug Administration ( FDA), the use of IV t- PA in acute stroke remains restricted because of the very short treatment window ( 3 hours), a widespread lack of expertise, and safety issues with a relatively high incidence of intracerebral hemorrhage and protocol violations. The administration of IA thrombolytics directly into occluded intracranial arteries has an extended treatment window of up to 6 hours after cerebral infarction ( 28,79,80), but this use is even more limited because of reliance on the presence of an experienced interventionalist. The same concerns and problems apply to the treatment of CRAO with IV thrombolysis. As stated earlier, IV thrombolysis is relatively easy and does not require highly specialized physicians. However, why take the risk of systemic administration of thrombolytics when only one small retinal artery is occluded? Thus, current thrombolysis for CRAO is mostly IA, requiring selective catheterization of the ipsilateral ICA and infusion of thrombolytics into the ophthalmic artery. When the ICA is occluded at 221 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Biousse et al angiography, the thrombolytic agent is administered into a branch of the external carotid artery, most often the maxillary artery, the facial artery, or a meningeal artery, with the hope that the drug will reach the central retinal artery through retrograde collateral circulation. Both t- PA and urokinase are being used and doses vary ( Table 5). In most cases, the IA thrombolysis is discontinued when there is clinical or angiographic evidence of revascularization of the central retinal artery. Heparin is then often given for a few days, followed by an anti- platelet agent. Is Thrombolysis Indicated in Treatment of Acute CRAO Case reports and studies evaluating the treatment of CRAO with IV or IA thrombolysis are detailed in Tables 4 and 5 and summarized in Table 6 ( 25,29- 61,65). Duplication of cases was found in a few articles, and these were not included in the summary shown in Table 6 ( 34,38, 40,41) ( only the most recently published articles by the same authors were included [ 35,53]). The evidence is impaired by several shortcomings. 1. There are no controlled trials. The main criticism of the previously published works on this subject is the lack of a single controlled clinical trial ( 51,62,63). Indeed, in all studies published to date, the visual outcome of patients with CRAO who were treated with thrombolysis has been compared to the outcome of a group of patients receiving various conservative treatments or to the presumed natural history of CRAO. Between 10% and 35% of patients with acute CRAO show visual improvement afterward, depending on how visual improvement is defined. Given that only a major improvement in vision would warrant an aggressive treatment such as thrombolysis, we have included in our summary analysis only those cases in which the authors described either " full recovery of vision" or improvement by at least 4 Snellen lines. Although some series have included patients with BRAO, we included only those with CRAO. Table 6 shows that 50 ( 48.5%) of 103 patients with acute CRAO treated with IV thrombolysis and 87 ( 34.9%) of 249 patients treated with IA thrombolysis had obvious improvement of visual acuity ( at least 4 Snellen lines or " full recovery"). These results of thrombolysis for CRAO appear to be better than those suggested in studies evaluating the natural history of CRAO or the results with other conservative treatments. Although some authors have suggested that most improvement occurs in patients treated less than 12 hours after CRAO, a correlation between improvement and treatment delay was not found in one review ( 51). It is difficult to perform any analysis on such a heterogeneous group of studies, and many reports do not provide enough details. Our linear regression analysis of the relationship between improvement and treatment delay showed no significant relationship. 2. There are many publication biases. It is likely that case reports and nonconsecutive small case series were only published because of relatively good outcomes and that complications of thrombolysis are under- reported ( Table 6). The existing literature reports, therefore, probably overestimate the effect of thrombolysis in CRAO and underestimate the risks of using thrombolysis in patients with CRAO. 3. Thrombolysis is often performed late after the onset of CRAO. It has been suggested that the retinal tolerance time to acute ischemia is less than 240 minutes ( 4 hours) ( 81). Experimental retinal ischemia in monkeys showed that the retina can survive for approximately 100 minutes without arterial blood flow ( 81) and up to 3 or 4 hours when there is collateral circulation providing residual blood flow to the ischemic retina ( 82). The treatment window for cerebral infarction is 3 hours for IV thrombolysis ( 28,78) and 6 hours for IA thrombolysis ( 28,79,80). Although experiments evaluating the retinal tolerance time to ischemia were performed in rhesus monkeys and may not reflect exactly what is happening in humans with acute CRAO, it is likely that the treatment window does not exceed 6 to 12 hours, even in cases of incomplete CRAO when there is residual circulation ( 62,63,82). Therefore, there is no reason to think that revascularization procedures performed after 12 hours of retinal ischemia should have any effect on visual outcome. Even so, thrombolytics have been administered up to 14 days after acute CRAO ( Table 6) ( 44). Patients with up to 20 hours of visual loss are being included in the EAGLE study ( IA thrombolysis is administered within 24 hours of visual loss) ( 65). This relatively large treatment window was chosen because retrospective reports had suggested an effect of thrombolysis even 24 hours after visual loss ( 49,51,53), and it was necessary to ensure recruitment of patients into the study. However, the same investigators have suggested that visual outcome is better when thrombolysis is performed within 4 hours ( 60), 6 hours ( 53,54), 7 hours ( 40), and 12 hours ( 25) after CRAO. It has also been emphasized that the visual prognosis is poor when thrombolysis is administered more than 20 hours after CRAO ( 41). Another factor associated with a better outcome is the severity of the CRAO ( Table 2). Patients with incomplete CRAO ( stages 1 and 2) probably have better collateral circulation and a longer tolerance of ischemia and may have a longer therapeutic window ( 4,53,66). 4. The treatment protocol has varied greatly. The main differences in treatment protocol among reported series are the route of administration and the type of thrombolytic agent used. IV streptokinase was used in early studies and has now been abandoned. Both t- PA and 222 © 2007 Lippincott Williams & Wilkins Central Retinal Artery Occlusion J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 urokinase ( used mostly outside the United States) are now routinely used with similar results. The largest number of patients were reported by German investigators who favor IA thrombolysis ( 38,40,41,43,49,52,53). Selective thrombolysis into the ophthalmic artery seems a good choice to reduce the rate of cerebral and systemic hemorrhage. The dose of the thrombolytic agent is usually adjusted on the basis of revascularization of the retinal arteries evaluated on ophthalmoscopic examination ( monitored during the procedure) or angiography. Table 6 emphasizes the main differences between patients treated with IV and IA thrombolysis. The visual outcome and the complication rate has been similar in CRAO groups treated intravenously and intra- arterially, suggesting that IV thrombolysis ought still to be considered. As expected, systemic and cerebral hemorrhages were more common in the IV group, and cerebral TIAs and infarctions were more common in the group treated with IA thrombolysis. According to the authors describing these ischemic complications, the selective catheterization of the ICA and ophthalmic artery was directly responsible for distal cerebral emboli. In most of these cases, an additional dose of the thrombolytic agent was administered immediately through the same catheter into the occluded cerebral artery and many neurologic deficits resolved ( and were reported as TIAs). The EAGLE study ( 65) was initiated by German investigators who have the largest experience with IA thrombolysis, and their protocol involves selective catheterization of the ipsilateral ICA with infusion of the thrombolytic agent ( t- PA, maximum dose of 50 mg) directly into the ophthalmic artery where possible ( Table 7). 5. The outcome measures vary greatly from one study to another. Most studies have used only visual acuity to measure visual outcome. Visual fields and retinal fluorescein angiography are being performed in the EAGLE trial ( Table 7) ( 65). However, these tests are time- consuming, and physicians are confronted with the choice of documenting the visual function and retinal appearance or treating the patient rapidly to reduce the time to treatment. 6. CRAO results from many disorders with varied prognoses. Although the cause of CRAO has not been reported in most studies, the pathogenesis of the CRAO may play a role in visual outcome and in the efficacy of thrombolysis. As emphasized by Hayreh ( 63,82), thrombolytics would be unlikely to provide benefit when there is a visible calcific embolus obstructing the central retinal artery. In addition, the presence of a patent cilioretinal artery probably influences visual outcome and should be noted. Finally, pretreatment evaluations rarely include imaging of the ICA other than the angiogram done during selective catheterization of the ophthalmic artery. It has been emphasized that the most common cause of CRAO is ipsilateral carotid atheroma, and there are numerous cases described in which thrombolytics had to be administered in a branch of the external carotid artery because of ipsilateral ICA occlusion or severe stenosis. The efficiency of such a protocol in the delivery of thrombolysis to an occluded retinal artery remains unknown. IS THE EAGLE TRIAL GOING TO PROVIDE IMPORTANT INFORMATION? The EAGLE study is the first prospective randomized clinical trial evaluating the effect of IA t- PA compared with conservative treatment ( Table 7) ( 65). This study should answer questions about the natural history of CRAO and the efficacy and side effects of IA thrombolysis. However, there is no true placebo arm, as patients who are not treated with thrombolysis receive some of the so- called conservative treatments, including ocular massage, therapies to lower intra- ocular pressure, aspirin, heparin, and isovolemic dilution. Although many investigators assume that " conservative treatment" is equivalent to " natural history," it would certainly have been more powerful to compare thrombolysis to the true natural history of CRAO ( 82). Subgroup analyses will be necessary for definitive interpretation of the results ( based on stage of CRAO, baseline visual function, residual retinal vascularization on angiography, and mechanism of CRAO). Because the treatment window is large, there will be a need for subgroup analyses, as it is probable that most improvement will be seen among those treated early ( 82,83). The EAGLE study was initiated in 2002, and 16 centers from Germany, Austria, and Switzerland have been actively including patients. The investigators calculated they would need to include 200 patients ( 100 in each group) to reach significance. However, even in these countries where thrombolysis for CRAO is well accepted and almost routinely performed, only 47 patients had been included by April 2005 ( 65) and 64 patients by August 2006 ( N. Feltgen, personal communication, October 2006). We will probably have to wait a few more years for the final results of this study. IN ADVANCE OF THE REPORT OF THE EAGLE TRIAL, HOW SHOULD CRAO BE MANAGED? There is currently not enough evidence to offer thrombolysis to all patients with acute CRAO. Caregivers have the option of enrolling patients in the EAGLE trial or in an IA treatment trial being conducted at The Johns Hopkins University under the auspices of Neil R. Miller, MD. Given the large number of published cases and the apparent relative safety and efficacy of thrombolysis in selected patients with acute CRAO, it is seems reasonable to 223 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Biousse et al TABLE 5. Previously published studies on the treatment of central retinal Authors, year, country Annonier et al, 34 1984, France Annonier et al, 35t 1988, France Tsai et al, 36 1990, USA Schumacher et al, 38 1991, Germany Mach et al, 39 1992, Ceskoslovakia Schmidt et al, 40 1992, Germany Schumacher et al, 41 1993, Germany Vulpius et al, 43 1996, Germany Ma et al, 44 1996, China Weill et al, 46 1998, France Weber et al, 47 1998, Switzerland Wirostko et al, 48 1998, USA Richard et al, 49 1999, Germany Padolecchia et al, 50 1999, Italy Beatty and An Eong, 2000, UK Framme et al, 52 2001, Germany Number of patients with CRAO ( age) 2 pts ( 27, 64 y)* 5 pts ( 25- 67 y)* 1 pt ( 32 y) 6 pts ( 46- 77 y)$ 1 pt ( 34 y) 14 pts ( 46- 87 y) received thrombolysis^: 41 pts ( 44- 87 y) received conservative treatment alone ( 1- 12 h) 23 pts ( 46- 87 y)$ 9 pts ( 50- 83 y) 4 pts (< 70 y) 7 pts ( 20- 82 y) 17 pts ( 60.8 ± 15.2 y) thrombolysis + conservative treatment vs 15 pts conservative treatment alone 1 pt( 65 y) 46 pts ( 58 ± 16 y) 3 pts ( 62- 76)] Meta- analysis of 16 studies: 100 relevant pts who underwent IA thrombolysis for CRAO ( 19- 87 y) 17 pts thrombolysis ( 40- 84 y) vs 45 pts conservative treatment Type of study Case reports Retrospective Case report Retrospective Case report Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Case report Retrospective, systematic treatment and evaluation Retrospective Meta- analysis Retrospective artery occlusion with intra- arterial thrombolysis Treatment Conservative treatment None None None NA NA All patients received conservative therapy; only 14 patients received thrombolysis NA IV pentoxifylline for 10 d NA None Anterior chamber paracentesis, acetazolamide None None None In some studies, patients received both conservative treatment and fibrinolysis Decrease of IOP, improvement of rheological conditions protocol Thrombolysis IA urokinase ( ICA) IA urokinase ( 2 pts) IV urokinase ( 2 pts) IV streptokinase ( 1 pt) IA urokinase ( ophthalmic artery) IA urokinase, heparin IA urokinase 11 pts: IA urokinase:]: 3 pts: 30 mg IA t- PA ( ICA), heparin IA urokinase IA t- PA IA t- PA, heparin, aspirin IA urokinase IA urokinase heparin, aspirin IA urokinase " anticoagulation" IA urokinase, heparin IA t- PA, heparin IA t- PA 42 pts: IA urokinase 52 pts: t- PA heparin IA t- PA 224 © 2007 Lippincott Williams & Wilkins Central Retinal Artery Occlusion J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Delay in thrombolsis < 4h 3- 11 h NA 5- 60 h 6h 4- 60 h 4- 60 h 10- 37 h 7- 14 days 9- 20 h < 6h 4h 3^ 11 h 4.5- 6.5 h 3- 60 h ( mean 11.6 ± 8.7 h) 4- 11 h Results 2/ 2 pts had mildly improved VA 4/ 5 pts had improved VA > 4 Snellen lines Partial restoration of vision All pts had improved VA; 2/ 6 pts recovered completely Pt had " improved VA" 8/ 14 thrombolysis pts had improved VA; 3/ 8 thrombolysis pts had improved VA > 8 Snellen lines ( all were treated within 7 h after CRAO); Almost no improvement in conservatively treated pts 3/ 23 pts had full recovery; 3/ 23 pts had improved VA > 8 Snellen lines; 2/ 23 pts had improved VA > 4 Snellen lines 5/ 9 pts had improved VA > 5 Snellen lines 2/ 4 pts had improved VA 5/ 7 pts had improved VA a 4 Snellen lines 3/ 17 patients had full recovery after thrombolysis; 2/ 17 pts had improved VA > 6 Snellen lines Improvement from count fingers to 20/ 20 7/ 46 pts had improved VA > 8 Snellen lines; 12/ 46 pts had improved VA> 4 Snellen lines 3/ 3 pts had improved VA; 2/ 3 had " complete recovery of vision" 14/ 100 pts had full recovery; 27/ 100 pts had VA > 20/ 40 of vision; no effect of delay in treatment on visual outcome; pts with better VA had better outcome 4/ 17 pts treated with thrombolysis had improved VA by > 2 lines; 16/ 45 pts treated conservatively had improved VA by > 2 lines Complications of fibrinolysis None None None 1 pt with groin hematoma None 1/ 14 pts had a TIA 2/ 23 pts had TIAs, 1/ 23 pt had groin hematoma None None None 2 pts with TIA None 2 pts with TIA None Complications in 4/ 100 pts: 1 pt with groin hematoma; 3 pts with minor cerebral infarctions Complications in 3/ 17 pts: 1 pt with cerebral hemorrhage; 2 pts with minor cerebral infarctions Continued on next page 225 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Biousse et al TABLE 5. ( Continued) Authors, year, country Schmidt et al, 53 2002, Germany Fernandez et al, 2002, Spain Butz et al, 56 2003, Germany Switzerland Tagawa et al, 58 2005, Japan Yao et al, 59* 2005, China Arnold et al, 60 2005, Switzerland Pettersen et al, 61 2005, Canada Feltgen et al, 65 2006, Germany, Switzerland, Austria Number of patients with CRAO ( age) 62 pts thrombolysis^: vs 116 pts conservative treatment ( 18- 89 y) 5 pts thrombolysis ( 47- 73 y) vs 7 pts conservative treatment ( 57- 81 y) 22 pts ( 40- 84 y) 1 pt ( 79 y) 13 pts ( 38- 72 y) 37 pts thrombolysis + conservative treatment ( 23- 83 y) vs 19 pts conservative treatment alone ( 33- 81 y) 8 pts ( 59- 77 y) 47 pts ( 18- 75 y) A, artery; CRAO, central retinal artery occlusion; IA, Type of study Retrospective, systematic treatment and evaluation Retrospective Retrospective Case report Retrospective Retrospective Retrospective Prospective randomized multicenter clinical trial Treatment protocol Conservative treatment Ocular massage, anterior chamber paracentesis, isovolemic hemodilution, acetazolamide, pentoxifyllin, aspirin, treatment of systemic hypertension Ocular massage, anterior chamber paracentesis, acetazolamide, topical medications to decrease IOP, inhalation of 02/ C02, aspirin, retrobulbar injection of papaverine Anterior chamber paracentesis ( 1 pt) Hemodilution ( 1 pt) None None Anterior chamber paracentesis, acetazolamide, heparin, aspirin 4/ 9 anterior chamber paracentesis; 1/ 9 ocular massage Randomization between conservative treatment and thrombolysis, then heparin for 5 days for all patients Ocular massage, topical medications to lower IOP, acetazolamide, aspirin, heparin, hemodilution Thrombolysis IA t- PA or urokinase anticoagulation IA urokinase heparin 7pts: IA urokinase; 15 pts: IAt- PA, heparin IA urokinase 6 pts: IA urokinase; 7 pts: IV urokinase IA urokinase IA t- PA IA t- PA intra- arterial; ICA, internal carotid artery; IOP, intraocular pressure; IV, intravenous; In most studies, the investigators monitored the fundus and the ophthalmic artery perfusion during the infusion of thrombolysis. Thrombolysis * The patients published by Annonier et al in 1984 ( 34^ 1 are also included in the article published by the same author in 1988 ( 35). f Studies also including patients treated with intravenous thrombolysis. ifSome patients were reported on more than once in studies from the same German are included in the article published by Schumacher et al in 1993 ( 41). No details were group [ Schumacher et al, 1991 ( 38); Schmidt et al, 1992 ( 40); provided in the article published by Schmidt et al in 2002 ( 53). 226 © 2007 Lippincott Williams & Wilkins Central Retinal Artery Occlusion J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Delay in thrombolsis Results Complications of fibrinolysis Mean 10.8 ± 9.5 h 10/ 62 pts with " distinct visual improvement"; visual outcome better in Thrombolysis group: thrombolysis within 6 h of CRAO Complications in 2/ 62 pts: 1 pt with TIA; 1 pt with cerebral infarction 11 h 4/ 5 pts treated with thrombolysis had improved VA > 4 Snellen lines None 4- 11 h NA 5- 38 h < 6h 9/ 22 pts had improved VA: 1/ 22 pt with normal VA ( treated within 4.5 h); 6/ 22 pts had improved VA > 8 Snellen lines; 2/ 22 pts had mild improvement Improvement of VA by 6 Snellen lines IA group: 3/ 6 pts had improved VA by a 4 Snellen lines; 2/ 6 pts had improved VA by > 2 lines; IV group: 1/ 7 pts had improved VA by 2 lines 8/ 37 pts treated with thrombolysis had improved VA > 20/ 30 ( better if treated < 4 h after CRAO); No improvement in 19 pts treated conservatively Complications in 4/ 22 pts: 2 pts with TIAs; 1 pt with intracerebral hemorrhage; 1 pt with massive cerebral infarction None None Complications in 3/ 37 pts: 2 pts with TIA; 1 pt with minor cerebral infarction 6- 18 hrs < 20 h for inclusion (< 24 h for treatment) 3/ 8 CRAO pts had improved VA by 2: 2 Snellen lines; 3/ 8 pts had improved VA by 1 line; All pts with persistent VF defects ( Goldmann) Pending ( study ongoing) None NA NA, not available; pt, patient; TIA, transient ischemic attack; VA, visual acuity; VF, visual field. was usually discontinued when reperfusion of retinal arteries or ophthalmic artery was seen on funduscopic examination or on the angiogram. Schumacher et al, 1993 ( 41); Schmidt et al, 2002 ( 53)]. The patients published by Schumacher et al in 1991 ( 38), and by Schmidt et al in 1992 ( 40) 227 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Biousse et al TABLE 6. Summary of previously reported CRAO cases treated with intravenous or intra- arterial thrombolysis Intravenous thrombolysis* Intra- arterial thrombolysisf Total cases Delay of treatment after CRAO ( range) Reported complications Improvement in visual acuity ( at least 4 Snellen lines) Improvement in visual acuity by at least 4 Snellen lines ( but not > 8 Snellen lines) " Full recovery" or visual acuity improved by > 8 Snellen lines 103 1 h- 10 days ( mean: 16 ± median: 6 h) 12.6% ( 10 hemorrhages) - 2 fatal, 1 shock 27 h, 48.5% 34% 14.5% 249 3 h- 14 days ( mean: 10.3 ± 8 h median: 8 h) 10% 12 TIAs, 6 minor cerebral infarctions 2 severe cerebral infarctions 2 cerebral hemorrhages 3 groin hematomas 87/ 249 ( 34.9%) 19.3% 15.6% "" Various doses of t- PA, urokinase, or streptokinease. f Selective into the internal carotid artery, into the opthalmic artery, or into a branch of the external carotid artery. TABLE 7. Summary of the European Assessment Group for Lysis in the Eye ( EAGLE) Trial* Inclusion criteria Exclusion criteria Randomization of patients between two parallel treatment regimens Primary end point Secondary end points Age 18- 75 years CRAO not older than 20 hours ( so that the thrombolysis is administered within 24 hours of vision loss) Visual acuity worse than 20/ 60 in the affected eye Branch retinal artery occlusion Cilioretinal artery supplying the macula in the affected eye Serious general disease " Conservative treatment" ( ocular massage, lowering intraocular pressure with topical ( 3- blocker and acetazolamide, aspirin, heparin, isovolemic hemodilution if hematocrit is > 40%; Intra- arterial ( ophthalmic artery) thrombolysis with t- PA ( maximum dose of 50 mg), followed by heparin for 5 days Visual acuity and funduscopic examinations repeated every 15 minutes by an ophthalmologist during the procedure Visual acuity 1 month after therapy ( compared with pretreatment visual acuity) Change in visual field ( using Goldmann perimetry) Effect of therapy on the retinal circulation evaluated with fluorescein angiography Safety of the two treatments Identification of prognostic factors ( time between onset of CRAO and treatment, stage of CRAO, preexisting systemic diseases) * Prospective, controlled, randomized study; multicenter study ( 16 participating centers from Germany, Switzerland, and Austria). 228 © 2007 Lippincott Williams & Wilkins Central Retinal Artery Occlusion J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 consider this treatment in CRAO evaluated within a few hours of onset, especially if the patient was previously functionally monocular. A survey of adults with normal vision evaluating patients' preference for the treatment of CRAO ( 85) 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 visual acuity 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 ( 85). Even if the EAGLE trial confirms the efficacy of IA thrombolysis for the treatment of acute CRAO, it is hard to imagine that IA thrombolysis would become a routine treatment for CRAO. Were acute visual loss to be immediately diagnosed as CRAO and the patient referred to a highly specialized center with immediate access to the most experienced interventionalist, treatment would still probably not be administered within 6 hours after the onset of visual loss in the majority of cases. 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