THROMBOLYTIC THERAPY FOR CENTRAL RETINAL VEIN OCCLUSION: RESULTS OF A PILOT STUDY

BY Michael J. Elman, MD
ABSTRACT

Objective: To evaluate the feasibility of conducting a randomized, controlled trial of thrombolytic therapy for central retinal vein occlusion (CRVO) using tissue plasminogen activator (TPA); to establish relative efficacy and safety of various dosing regimens.
Design and Patients: Ninety-six patients with CRVO were treated with TPA between May 1986 and December 1992. Prior to patient enrollment, a standardized, detailed protocol was developed for evaluation and treatment of all patients. This included standard protocols for determining eligibility, reporting complications, performing photography and electroretinography, and measuring visual acuity.
Main Outcome Measures: Best corrected visual acuity at 6 months, systemic and oplhhalmic treatment complications.

Results: At 6 months' follow-up, 42% (n=89) of eyes gained three or more lines of vision from pretreatment levels (average gain, 5.1 lines), 37% remained stable, and 21% lost three or more lines. Of eyes with 20/100 or worse pretreatment vision (n=32), 59% gained three or more lines vision (average gain, 6.4 lines), 31% remained stable, and 9% lost three or more lines. One patient suffered a fatal stroke. Three patients developed intraocular bleeding during TPA administration.

Conclusion: Thromobolytic therapy with TPA appears to be a promising, albeit risky, new treatment; conclusive evaluation of safety and efficacy awaits a multicenter, randomized, clinical trial; feasibility of such a trial has been established by this study.

TR. AM. OPHTH. SOC. VOL. XCIV, 1996

472

Elman
INTRODUCTION

DESCRIPTION AND COURSE

Central retinal vein occlusion (CRVO) is a common retinal vascular problem that has an often devastating impact on vision. The fundus appearance can be quite dramatic, with varying degrees of intraretinal hemorrhages scattered in all four retinal quadrants, venous dilation and tortuosity, and disc swelling. Precise incidence and prevalence data are not available for the United States. However, in Israel, retinal vascular occlusion was estimated to affect 4.5 persons per 10,000 population; CRVO was estimated to account for half of these patients (personal communication, Yuval Yassur, May 1987). Taking these estimates as an approximation, there may be as many as 60,000 cases of CRVO in the United States. Data on the incidence of new cases of CRVO are not available. Two types of CRVO have been described. The descriptive terminolofor gy these two types has led to some confusion and includes complete versus incomplete, venous stasis retinopathy versus hemorrhagic retinopathy, nonischemic versus ischemic, and perfused versus nonperfused.' The CRVO type, based on fluorescein angiographic capillary perfusion, carries prognostic value. Eyes with ischemic CRVO, also termed "severe" or "complete" CRVO, are at greatest risk for the serious complications such as neovascular glaucoma, retinal neovascularization, and vitreous hemorrhage.2 Eyes with ischemic CRVO rarely present with visual acuity better than 20/100.3- Final visual acuity is usually 20/200 or worse in 94% of eyes, and about 70% to 80% of eyes are left with a final acuity of less than 20/400.2 Visual loss results from permanent capillary nonperfusion, macular edema, and/or secondary complications arising from ocular neovascularization. Overall, vision declines by three or more lines in 40% of CRVO eyes while improving in only 18%.2 Iris, angle, and retinal neovascularization frequently comnplicate ischemic CRVO.67 The reported incidence of iris neovascularization ranges from 58% to 82%. 8-12 Iris neovascularization can quickly progress to angle neovascularization. If angle neovascularization continues unchecked, 29% to 55% of patients develop neovascular glaucoma.38,2,3 Retinal neovascularization, although less common, arises in 5% to 18% of all ischemic eyes.14"5 Initial visual acuity in mild or perfused CRVO eyes, usually better than 20/100, may range from 20/20 to counting fingers."6"6"7 However, good initial visual acuity does not guarantee a favorable outcome; poor initial visual acuity is often associated with a poor visual outcome, usually

Thrombolytic Therapy for Retinal Vein Occlusion

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from chronic cystoid macular edema and varying degrees of macular ischemia."5"7"' Forty percent of eyes with mild CRVO will lose two or more lines of vision regardless of entrance vision. While retinal neovascularization rarely develops with perfused CRVO, approximately 7% to 17% of these eyes will progress to ischemic CRVO, thus acquiring the prognostic characteristics of ischemic CRVO.219,20 Established treatment of CRVO remains palliative, directed at stabilizing the eye by preventing catastrophic visual loss from complications such as neovascular glaucoma. To date, no safe and effective treatment exists for improvement of visual acuity. Current accepted treatment for CRVO with laser photocoagulation is directed at preventing catastrophic visual loss from complications such as neovascular glaucoma. However, photocoagulation does not improve the final visual prognosis above pretreatment levels.132124 The Central Vein Occlusion Study'2 found that grid laser photocoagulation to eyes with macular edema did not improve visual outcome.
HISTOPATHOLOGY AND PATHOPHYSIOLOGY OF CRVO

Von Michel21 was the first to correlate the clinical presentation of CRVO with pathologic changes in the obstructed central vein. Histopathologic studies point to thrombosis of the central retinal vein at the level of lamina cribrosa retrolaminar optic nerve as the cause of CRVO.'62' Once the thrombus is formed, the blood-retinal barrier breaks down, resulting in blood and fluid extravasation into the retina. A self-perpetuating spiral of increased edema and capillary closure develops. If enough capillaries close, retinal ischemia may liberate vasoproliferative factor in sufficient quantities to stimulate development of anterior or posterior segment neovascularization. When present in the macula, ischemia may also lead to partial, irreversible, or complete decrease in retinal function manifested primarily by decreased visual acuity. Histopathologically, thrombi of the central retinal vein appear similar in composition and origin to other venous thrombi throughout the body.28 In general, thrombi occur in the presence of stasis or in response to a vascular wall injury and represent the relative imbalance of thrombogenic and fibrinolytic pathways. Factor Xa converts prothrombin to thrombin in concert with calcium and factor V. Thrombin acts on fibrinogen to generate fibrin monomers and also acts indirectly to cross-link the fresh fibrin clot, entrapping erythrocytes and leukocytes and stabilizing platelet thrombi. Under normal physiologic conditions, thrombi generated in the course of hemostasis are limited by the fibrinolytic system through activation of plasminogen to plasmin. This fibrinolysis prevents extension of the throm-

and erythrocytes. review of the literature from that time is informative. At about 7 to 14 days after diagnosis. underlying health of the eye. these cells replace the thrombus with vascularized connective tissue. During this time. rapid restoration of normal retinal blood flow through clot dissolution might prevent further visual loss resulting from chronic complications of CRVO. prevention or moderation of further visual decline. During the 1950s and 1960s. following the onset of symptoms. fibroblasts. as well as of devastating complications such as neovascular glaucoma and retinal neovascularization. and inflammatory cells begin to invade the thrombus. Even if irreversible damage has occurred. A newly formed thrombus is composed of platelets. Despite these major shortcomings. this was statistically significant (X22dfF. fibrin. and lack of prospective data collection. Dissolving the thrombus (either through exogenous thrombolytic agents or through native thrombolysis) and preventing its re-formation (either through anticoagulation with heparin and coumadin or with antiplatelet therapy with aspirin) should effectively restore retinal blood flow and visual function. The thrombus extent. Thrombus formation and recanalization involves a series of steps. even if vision cannot be improved. would be desirable outcomes of such treatment.474 Elman bus and subsequent organization by proliferating endothelial cells and fibroblasts. Vannas and Ritta3l reported development of hemorrhagic glaucoma in 8 of 56 eyes treated with anticoagulants and in 20 of 66 untreated eyes. Eventually. A steady state is reached between clot deposition and clot dissolution. nonstandardized data collection. P = 0. ANTICOAGULATION Anticoagulation alone should tip the equilibrium between thrombolysis and thrombogenesis in favor of thrombolysis. This may take 3 to 8 months to complete. endothelial cells. re-establishing some degree of circulation. Finally. these studies suffer from nonrandomized treatment allocation. For example. Patients requiring treatment in .036). and activity of the endogenous fibrinolytic system all contribute to determine the final outcome of the CRVO. Thus. leukocytes. viability of collaterals. several investigators29-31 reported results with anticoagulation therapy. such as long-standing cystoid macular edema and retinal ischemia.4. invading endothelial cells form a network of vascular channels. careful classification of CRVO type had not been developed 40 years ago when critical evaluation of anticoagulation for treatment of venous occlusive disease was initiated. statistical analysis of data collected was not performed. Further. Unfortunately.

THROMBOLYTIC THERAPY Streptokinase Treatment Several investigators32-m have reported on treatment with thromoblytic agents in CRVO. Forty CRVO patients with symptoms for less than 7 days were randomly assigned to receive treatment with either streptokinase and anticoagulation therapy (20 patients) or to a natural history control group (20 patients). Although there was no difference in the initial visual acuity. and specific risk factors in patients who developed complications were not described. 1% of the patients had a major complication and in "0. duration of therapy.3' four patients had major complications. To date. only 5 of the treated patients (25%). anticoagulation took a secondary place in the therapeutic armamentarium. In the series reported by Vannas and Ritta. two patients died.5% the cause of death could probably be attributed to therapy. patients were anticoagulated first with heparin and then with coumadin for 6 months. methods for maintaining anticoagulation control. experienced deterioration in vision. In the eyes with entrance visual acuity of 3/60 (20/400) or better. There were no systemic complications. all three eyes progressed to functional blindness. 46% of treatment eyes and 13% of control eyes had gained three or more lines at 1-year follow-up. Unfortunately.3 However. three eyes in the treatment group (15%) sustained severe breakthrough vitreous hemorrhage while receiving streptokinase.01). the treatment group still showed a statistically significant improvement in vision when compared with the control group. Furthermore. On the basis of these data.03). this treatment has never been critically evaluated using proper experimental design and standardized treatment and evaluation protocols. With the advent of local therapies. compared with 12 of the controls (60%). the significant improvement in final visual acu- .35 The results of this study suggest that this approach is promising.Thrombolytic Therapy for Retinal Vein Occlusion 475 another hospital for bleeding complications were classified as major complications. one of "an apoplectic insult" and one of "a retroperitoneal hemorrhage. controlled trial using thrombolytic agents and anticoagulant therapy in treating CRVO has been conducted." Unfortunately. only one randomized." Thus. Notwithstanding these three complications. Altogether. 46% of treated eyes and 27% of control eyes remained within three lines. and only 8% of treated versus 60% of control eyes had lost three or more lines of vision (Exact P=. all three breakthrough vitreous hemorrhages occurred in severely ischemic CRVO eyes. After 3 days of intravenous streptokinase therapy. final vision was significantly better in the treatment group (P<0.

despite the inclusion of three therapeutic complications and a small sample size. In contrast. plasmin. to an active serum protease. the value of scatter laser treatment in controlling complications from ocular neovascularization from any retinal disease had yet to be established. plasminogen. Today. Thrombolysis occurs by the sequential conversion of a circulating zymogen. In addition.476 Elman ity in the treated group. First. Patients with CRVO who may require streptokinase subsequently for life-threatening thrombotic disease. Although no systemic complications developed in this small study. that in turn proteolytically cleaves fibrin within thrombi. Tissue Plasminogen Activator Pharmacology and Therapeutic Complications. Physiologic or pharmacologic thrombolysis is mediated by one of a number of plasminogen activators. modem diagnostic and therapeutic techniques would identify the ischemic eyes at greater risk for intraocular bleeding and temper this complication should it arise through vitrectomy and laser photocoagulation. patients are at greater risk for systemic bleeding for a longer period of time with streptokinase than with clot-specific lysis agents. may be denied the lifesaving therapeutic benefits of streptokinase owing to its prior use. the potential systemic complications of streptokinase probably did not justify its widespread use. vitreous microsurgery permits safe and easy removal of vitreous hemorrhage. streptokinase is antigenic. Thus. intraoperative or postoperative photocoagulation can control underlying ocular neovascularization in a timely fashion. Third. Ideally. massive intravitreal hemorrhage alone resulted in permanent visual loss. in the previtrectomy era. pharmacologic thrombolysis is initiated with a plasminogen activator capable of efficiently generating plasmin on the surface of thrombi without inducing plasminogen . when this study was executed (early 1970s). such as acute myocardial infarction. Intraretinal bleeding may have resulted from subtle. each with characteristic pharmacokinetics and specificity for plasminogen activation in the presence of fibrin and affinity for circulating inhibitors. neither technique was used in the study. Indeed. such as tissue plasminogen activator (TPA). that have a short circulating half-life. Streptokinase and urokinase induce a systemic lytic state for almost 24 hours after discontinuation. Advances in patient care since the time of this study warrant comment. points to the promise of thrombolytic agents in the treatment of CRVO. retinal neovascularization that was clinically undetected. fluorescein angiography and electroretinography were not developed sufficiently to identify markedly ischemic eyes at risk from breakthrough bleeding. Second.

TPA has undergone extensive clinical study and has been approved by the Food and Drug Administration for early treatment of acute myocardial infarction. peripheral arterial occlusions.Thrombolytic Therapyfor Retinal Vein Occlusion 477 activation in the circulating blood and hence a fibrinolytic state with its attendant risks of hemorrhage.50' In summary. Fluorescein angiography was performed with a fundus camera (TOPCON TRC-WT) before treatment and at intervals of 4 hours and of 1. Conversion of plasminogen to plasmin is enhanced markedly in the presence of fibrin (Km =0. Pupils were dilated with phenylephrine hydrochloride (2. and Khoobehi62 of the LSU Eye Institute in New Orleans investigated the efficacy of TPA in lysing experimentally induced retinal vein thrombi. 4.3940 lacks immunogenicity. Sodium fluorescein (10%) was injected intravenously (0. TPA elicits rapid and effective thrombolysis. Fourteen albino New Zealand rabbits (28 eyes) weighing 2 to 3 kg each were anesthetized with an intramuscular injection of 35 mg/kg of ketamine hydrochloride and 5 mg/kg of xylazine hydrochloride for all procedures. Occlusion of the retinal veins was performed by photothrombosis. Peyman. The incidence of life-threatening stroke on intravenous TPA ranges between 0. TPA is a naturally occurring serum protease of 527 amino acids (MW = 68. effective. In comparison with other thrombolytic agents. 3. activation of plasminogen induced by TPA is localized by generation of plasmin primarily within or on fibrin thrombi.5%.1 mL/kg) immediately prior to angiography.5%) and tropicamide (1%) eye drops. Pharmacologic thrombolysis with TPA has been studied most extensively in patients with acute coronary thrombosis and myocardial infarction.37'8 exhibits considerable clot selectivity. Rose Bengal solution at a concentration of 30 mg/mL was prepared by dis- . TPA in the Treatment of Experimental Retinal Vein Occlusion.'. It is a single polypeptide chain that is converted rapidly to a twochain form with the chains joined by a disulfide bond after cleavage of the Arg-278-Ile-279 bond by plasmin. deep venous thrombosis. TPA does not promote activation of plasminogen in the absence of fibrin (Km=65 pM). unstable angina.4' has a short half-life in the circulation. and safe treatment of thrombosis.4% and 1. and 15 days after treatment. TPA exhibits biochemical and pharmacodynamic properties needed for rapid. 2. and cerebral thromboembolic disease. In contrast to other activators.45-49Thrombolysis with TPA has also been employed for treatment of pulmonary emboli.000).4 permitting prompt restoration of hemostatic integrity after discontinuation of treatment needed prior to invasive procedures or to counteract bleeding.' and manifests little fibrinogenolysis.16 pM) without significant change in catalytic rate.3940 Thus. 7. Drs Oncel.

The endothelial damage is mediated by electron-state transition occurring at essentially physiologic temperatures (Herman.478 Elman solving the Rose Bengal (MW 11018. The artery adjacent to the vein was not affected by this treatment. embedding in historesin. The eyes were enucleated and prepared for light microscopy by fixing in 3% glutaraldehyde and 2% paraformaldehyde. Photocoagulation pyrolitic effects are unnecessary for the induction of vascular occlusion in the photothrombotic technique. Focal vascular occlusion was uniformly produced by argon . Retinal veins were occluded by intravenous injection of this solution at a dose of 40 mg/kg of body weight followed by irradiation of the vessels with an argon laser beam (power. 3. St Louis). This method utilizes much lower irradiation intensities. To correlate the morphologic alterations with clinical observations. 2. Bedrich Chemical Co.2 seconds) using a contact lens. Photothrombosis was used to occlude the retinal vein because it is intrinsically more efficient than photocoagulation. and staining with toluidine blue. Immediately after this procedure and before injection of TPA (Invitron. 1983).5 mg/kg) administered intravenously. beam spot size. Milwaukee) in normal saline solution and filtering with a 0. Eyes were excluded from this study if the treated vessels were only partly occluded. thereby avoiding the damaging levels of thermal energy associated with photocoagulation. Engorgement of the vein tract peripherally to the laser marks with venous circulation shunted away from the occluded vessel was noted.45-pm sterile Millipore filter (Medford. 50-pm diameter. Mass). Occlusion was confirmed by angiography. Control animals (six rabbits. 7. and 15 days after the treatment. rabbits were euthanized by intravenous injection of 0. 4. Heat-induced damage is neither necessary for vascular occlusion nor desirable. Retinal veins were irradiated with an argon-dye laser (Coherent Medical 920). Fluorescein angiography was repeated to determine the patency of the vessel at intervals of 4 hours and 1. duration. artified grade. eight randomly selected rabbits (16 eyes) with occluded retinal veins were treated with TPA (0. Five to ten spots were delivered at the blood column of the retinal vein at a distance of 1 disc diameter from the disc until the blood flow in the thrombosed vessel was completely arrested. The vessel occlusion is achieved by means of a photochemical reaction operating at physiologic temperature. 0. To induce thrombolysis and prevent thrombus organization. Platelet adhesion is followed by degranulation and intense physiologically mediated aggregation to the point of complete thrombotic vascular occlusion. 90mV to 120 mV.3 mL/kg of T-61 euthanasia solution. 12 eyes) received intravenous normal saline solution. fluorescein angiography was performed.

and the availability of TPA. The design involved TPA treat- . The fluorescein angiograms were graded to assess the amount of perfusion of the retinal vein. The main objective of this study was to gain experience with patient recruitment. Within 4 hours of photothrombosis.3%) treated with normal saline solution.0001. and no evidence of neovascularization was seen in the fluorescein angiograms. In the control animals. the presence of shunts. the retinal vein was patent in all 16 eyes treated with intravenous TPA. there was a marked dilation of the vein peripheral to the site of occlusion. the second angiogram (4 hours after injection with normal saline solution) showed complete occlusion (grade 0) in 11 eyes and partial (grade 2) perfusion in on eye. and it showed complete occlusion of the retinal veins. with a confidence interval of 95%. Eight of the rabbits received intravenous TPA and six received intravenous normal saline solution. controlled trial. By day 7. a highly specific clot lysis agent with a short half-life in the circulation. and 3 signifying complete perfusion. The statistical significance. Hemorrhages were not a prominent feature immediately after occlusion. Immediately after occlusion. The initial fluorescein angiogram was performed immediately after photothrombosis and before therapy. large clumps of platelets. the author undertook a study designed to evaluate the feasibility of conducting a randomized. METHODS A pilot study with thrombolytic therapy for CRVO using TPA was conducted beginning in May 1986. the veins had reopened in all control animals. as evidenced by the lysis of the clot and the free course of dye throughout the area of photothrombosis. the potential efficacy of TPA in dissolving clots as seen experimentally. 2 meaning partial perfusion. was P<. and confluent intraluminal thrombosis. with narrowing of the vein proximal to the occlusion. and to determine the safety of the treatment in anticipation of a randomized. Vein occlusion was demonstrated by the lack of fluorescein filling.Thrombolytic Therapy for Retinal Vein Occlusion 479 laser-induced photothrombosis. The rabbits were observed for 29 days. according to the paired t-test. Examination by light microscopy showed damage to the vascular endothelium. Four hours postinjection. with 0 meaning nonperfusion. and engorgement of the veins above the occlusion. In light of the promising clinical results with streptokinase. to establish relative efficacy of various dosing regimens. retinal vein patency was noted in 16 eyes (100%) treated with TPA and one eye (8. clinical trial. 1 being penetration with minimal perfusion.

46 This regimen was potentially safer as well as more efficacious than the previous dose (group III. Eligibility criteria. II. to follow the dose established in the Thrombolysis in Myocardial Infarction (TIMI) Trial. and changing to a dose-per-weight schedule (group II. Recommended dosing schedules for TPA and anticoagulation during the follow-up period were modified three times over the course of the study.480 Elman ment of all eligible patients with a diagnosis of CRVO and follow-up of 6 months. two patients converted from perfused to nonperfused CRVO at 2 months posttreatment. and follow-up visits were designed and used for all patients. A comprehensive study protocol was developed prior to patient enrollment. and symptoms present for less than 6 months. Data collection forms for determination of eligibility. electroretinography. heparin for groups I. Systemic and ophthalmic exclusion criteria are listed in Tables I and II. lengthening the time of TPA administration. The study protocol was administered under the supervision of the author. evaluation of cardiovascular status. in response to patient data or other current information. In response to these complications. Enrolled patients were admitted to the Johns Hopkins Hospital Clinical Research Center. manifested by a sudden profound decrease in vision. and III. n = 10). The TPA dose was changed again. In this group of six patients. Food and Drug Administration and institutional review board approval were applied for and obtained. initially limited enrollment to eyes with perfused CRVO. Informed consent was required for inclusion in the study. a research nurse or physician's assistant was present at the patient's bedside throughout the entire TPA infusion. adding coumadin as an anticoagulant. a conservative dose with TPA was selected (group I) following the guidelines established by the study cardiologist. A study cardiologist determined systemic eligibility using set criteria. n = 19). Twelve patients were enrolled during the first year under this protocol. respectively. modified in the second year. best corrected visual acuity between 20/40 and 20/100. Retinal neovascularization developed in one and vitreous hemorrhage in the other. Initially. the author modified the protocol. Standard protocols for photography. provided that best corrected visual acuity was 20/800 or better and symptoms had been present for less than 1 month. From the second year forward. The author then decided to employ a sim- . and coumadin for groups II and III. reporting of complications. all eyes with CRVO were eligible (whether perfused or nonperfused ischemic). Treatment regimen (Table III) consisted of TPA and aspirin for all patients. and measuring of visual acuity (Macular Photocoagulation Study protocol)63were developed and followed.

2. on the basis of data from ongoing studies in Europe. 1 week. Both safety and ease of administration were improved with this regimen. 3. expecting that any treatment-related complications or improvement should be seen by 6 months. involving TPA followed by aspirin without any conventional anticoagulation (group IV. At each follow-up visit. n=55).Thrombolytic Therapy for Retinal Vein Occlusion TABLE I: MEDICAL EXCLUSION CRfIERIA 481 Uncontrolled hypertension (systolic blood pressure> 170 mm Hg or diastolic> 100 mm Hg) History of cerebrovascular accident or transient ischemic attack History of seizures Major closed trauma within 3 months Vaginal bleeding in postmenopausal woman Pregnancy based on positive serum beta human chorionic gonadotropin Concurrent thromboembolic disease Currently receiving anticoagulation therapy or a poor risk for anticoagulation therapy Currently receiving antiplatelet therapy or a poor risk for antiplatelet therapy Bleeding diathesis Gastrointestinal bleeding Internal surgery within last 3 months Hepatic failure Uncooperative behavior Study medications contraindicated Other active medical problems pler regimen. but owing to limited funding. 4. . and 6 months posttreatment. without coumadin. and 1. the author concentrated on the initial 6 months. best corrected visual acuity was measured. 5. Treated patients were examined 1 day. The author attempted to follow patients beyond 6 months. and slit-lamp examination.

75 are very good. A kappa greater than 0. To test the repeatability of this grading system. Neither grader had used this grading system before. color fundus photography. Fisher's exact test was used to compare proportions when the sample size was small. or fluorescein angiography gonioscopy.75 is considered excellent. which measures the degree of agreement between graders above that which would be expected by chance alone. was calculated to assess the repeatability of these gradings. and fluorescein angiography were performed. fundus examination with indirect ophthalmoscopy. Results were based on this independent masked grading. electroretinography. fundus photography. all photographs were graded independently by two graders.482 Elman TABLE II: OPHTHALMIC EXCLUSION CRITERIA Retinal or iris neovascularization Vitreous hemorrhage Diabetic macular edema or preproliferative diabetic retinopathy either eye Uncontrolled glaucoma or intraocular pressure >30 mm Hg Previous retinal vascular disease or macular disease Cataract extraction within last 6 months or YAG capsulotomy within last 3 days Prior photocoagulation Presence of any condition that requires use of systemic steroids and/or any drugs that affect the retina Any condition precluding reliable electroretinographic tracings. 100 sets of fluorescein angiograms and color fundus photographs from 20 patients were available for grading.64 To test the photographic protocol.6 and 0. visual acuities and changes in visual acuity were compared between groups using the Wilcoxon rank sum test and Spearman's rank correlation coefficient. Both individuals used open grading for the first 2 weeks of grading to train in this scheme. using the newly devised grading protocol for CRVO. The chi-square test was used to compare proportions between groups along with the chi-square test for trend when there was a natural ordering of the groups. kappas between 0. The kappa statistic. kappas between . all photographs were graded independently. Group means were compared using Student's t-test. tonometry. slit-lamp contact lens biomicroscopy. Thereafter.

Thronmbolytic Therapy for Retinal Vein Occlusion I I 483 c~~~~~ ~Qc u "000 .0 z 0~~ bi-cs4 0 F o b.00 0 bDt_to0 0~~~~~~~~~~ "L) Cv) E > b-0 00 > UD 0bJ -4 t" z 0 >~~~~~~~~~0 * -8~~~~~~0PLi 0~~~~~~~~~ ~ ~ ~ ~ - 4--j ~ ~ ~ ~ +~~~~~~~~"0 ~ ~~ ~ ~ ~ ~~ ~ 0 O V~~~~~~O O~~~0 z (0 0~~~~~~~~~~~~) a) -o 0 0 > (0 z 0~~~~~~~~~ 0~~~~~~~~~~~~~~~ .

40 and 0. Seventeen patients (18%) were under 40 years of age. less credit is given as the two gradings get farther apart.60 are considered to show fair to good agreement beyond chance. or areas where no retinal capillary bed can be seen. 1986. the percent agreement. retinal detachment in two. Sixty-five patients (68%) were male. 28 (29%) were over 60 years. whereas branch retinal vein occlusion was the cause in five. and a weighed kappa were calculated. Ten patients (10%) were treated within 7 days of onset of symptoms. and December 15. the kappa.1) years. a weight of 1 was assigned for exact agreement and a weight of 0 was assigned for the most extreme disagreement possible. The mean duration of symptoms before enrollment was 21 days. (2) nonperfusion. Twenty-four patients (25%) had visual acuity of less than 20/100 in the fellow eye at presentation. amblyopia in two. trauma in four. which are vessels that fail to fill on the angiogram but show blood on the corresponding color photograph. that difference is considered a complete disagreement. 30 (31%) were treated between 3 and 4 weeks of onset. In those five. This is a reasonable procedure when the scales are ordinal as they are here. 27 (28%) were treated between 15 and 21 days of onset. and glaucoma in one. All weights for disagreements in between were divided evenly between 0 and 1. Agreements in the grading of characteristics from the fluorescein . 24 (25%) were treated between 7 and 14 days of onset. each increasing grade indicates increase in severity of the lesion. For the weighed kappas. if the two graders disagree even by only one step on the grading scale.484 Elman 0. CRVO was the cause of decreased visual acuity in the fellow eye. In ten (42%). there was evidence of progression of visual loss with worsening of the fundus appearance. thus. RESULTS Between May 8. and five patients (5%) were treated with symptoms longer than 1 month's duration. The weighed kappa allows some credit to be given for gradings that differ by small steps. and (3) black vessels. By definition of kappa. 96 patients were enrolled in this study. Definitions of angiographic characteristics include (1) pruning. the weights for each lesion differ. The average age at enrollment was 56 (SD = 13. For each characteristic graded. The left eye was involved in 51 (53%) of patients and the right eye in 45 (47%). in which tributaries are missing from a branch vein and appear like a bush that has been pruned. depending on the number of categories in that particular grading scale. 1991.

ghost vessels.Thrombolytic Therapy for Retinal Vein Occlusion 485 angiograms are shown in Table IV. age.0%) developed intraocular bleeding during TPA administration. followup visits after 6 months. in eight (8%) the perfusion status could not be graded. Subgroups of the study population were analyzed to identify groups that might be at greater risk or might benefit more from the TPA treatment. the individual numbers for all seven fields are listed below. Only three patients (3.69 . Visual acuity data from the 6-month follow-up visit are reported on 89 patients. Visual outcome did not correlate with baseline perfusion status on fluorescein angiography (Table X). Seven patients missed their 6-month follow-up visit. Results are displayed for those patients returning annually.91 Black vessels .65 Nonperfusion . One patient (group 3). TABLE IV: AGREEMENT BETWEEN GRADERS FOR FLUORESCEIN ANGIOGRAMS CHARACTERISTIC Pruning UNWEIGHTED KAPPA WEIGHTED KAPPA . described subsequently).76 .77 A CRVO was considered ischemic if the pretreatment fluorescein angiogram demonstrated pruning. or capillary dropout greater than five disc areas. a 60-year-old white man with symptoms for 5 days. All patients had some oozing from previous venipuncture sites or subcutaneous ecchymosis from old bruises.85 . were not required. the median is initially reported. and 73 (76%) were nonischemic. One patient sustained a massive and fatal cerebral hemorrhage from treatment (case 2. Because many patients came from out-of-state. For the lesions graded on seven fields. sex. and duration of symptoms did not correlate with presenting vision or visual outcome. while encouraged. Treatment group. Fifteen eyes (16%) were graded as ischemic. developed a large inferior subretinal pigment epithe- . There was no difference in baseline characteristics between the seven lost to follow-up and the 89 patients who returned for their 6-month visit. Attempts to obtain follow-up information on these seven patients from their referring ophthalmologists were unsuccessful. Visual acuity results are displayed in Tables V through X.

TABLE V: NO. +Average lines gained. 5. 6.1.486 Elman AT BASELINE. 5. *Average lines gained.4.6. . (%) OF EYES WITH SPECFED VISUAL ACUI 6 MO. AND 1 YR VISUAL AcUmTY BASELINE 6 Mos 1 YR 16 (22) 20/20-better 20/25-20/40 20/50-20/100 5 (5) 19 (20) 39 (41) 20/125-20/200 20/250-5/200 <5/200 15 (16) 13 (14) 5 (5) 0 0 17 (19) 21 (24) 17 (19) 17 (19) 9 (10) 7 (8) 1 (1) 0 89 18 (25) 8 (11) 16 (22) 8 (11) 6 (8) Light perception No light perception Total 0 0 72 96 TABLE VI: CHANGE IN VISUAL ACUITY AT 6 MOS FROM BASELINE CHANGE ALL PATIENTS INITIAL VISION 20/64 OR WORSE INITIAL VISION 20/100 OR WORSE n 89 56 32 Gain of 3 or more lines 37°(42%) 33(37%) 19(21%) 30'(54%) 18(32%) 8(14%) 19*(59%) 10(31%) 3(9%) Stable within 3 lines Loss of 3 or more lines 'Average lines gained.

+Average lines gained.1.8. TABLE VIII: CHANGE IN VISUAL ACUITY AT 2. 4.Thrombolytic Therapy for Retinal Vein Occlusion TABLE VII: CHANGE IN VISUAL ACUITY AT 1 YR FROM BASELINE 487 CHANGE ALL PATIENTS INITIAL VISION 20/64 OR WORSE INITIAL VISION 20/100 OR WORSE 26 n 74 44 Gain of 3 or more lines 35*(47%) 28'(64%) 18$(69%) Stable within 3 lines Loss of 3 or more lines 21(29%) 9 (20%) 7 (27%) 18(24%) 7(16%) 1(4%) 'Average lines gained. +Average lines gained. 6. *Average lines gained. .3.4. 5. 4.8. 'Average lines gained.8. 5. 5. 3 AND 4 YRS CHANGE n 2 YRs 3 YRS 4 YRs 52 39 35 Gain of 3 or more lines 28'(54%) 17+(44%) 18*(51%) Stable within 3 lines Loss of 3 or more lines 9(17%) 13(33%) 9(26%) 15(29%) 9(23%) 8(23%) *Average lines gained.

94. p =.57 lial (RPE) hemorrhage that broke through into the vitreous several weeks later.488 IX: Elman TABLE CHANGE IN VISUAL ACUITY AT 1 YR CHANGE n TPA PATIENTS BASELINE 20/50-20/200 44 CVOS PATIENTS 72 Gain of 3 or more lines 21(48%) 4(6%) Stable within 3 lines Loss of 3 or more lines 10(23%) 59 (82%) 13(30%) 9(13%) CVOS.226. X2 (trend) = 4. His visual acuity improved three lines from baseline and was last recorded at 5/200 after 6 . This cleared without intervention over several months but recurred owing to a small area of traction adjacent to the disc. p = . Central Vein Occlusion Study. The hemorrhage was eventually removed surgically without complication.04 TABLE X: CHANGE IN VISUAL ACUITY AT 6 MO AND PERFUSION ON BASELINE FLUORESCEIN ANGIOGRAM* CHANGE ISCHEMIC NONISCHEMIC INDETERMINATE Gain of 3 or more lines 6 28 3 Stable within 3 lines 7 24 3 Loss of 3 or more lines 2 2 17 0 ox 4 = 2.

scleral buckling operation. There was no evidence of difference in the 6-month visual acuities in patients treated with TPA plus coumadin and aspirin (groups 2 and 3) versus TPA plus aspirin without coumadin (groups 1 and 4). The third patient (group 4). The vitreous blood was removed and the retina successfully reattached with a vitrectomy. aspirin was discontinued. when endoscopy revealed an erosive gastric lesion. an encircling scleral buckle. During the fifth hour of TPA infusion.5 years after treatment that required vitrectomy surgery. Before treatment. The second patient (group 4). his vision measured 20/200. Three weeks later. Five eyes (5%) required vitrectomy surgery. he developed breakthrough vitreous hemorrhage from an area of very ischemic. at 6 years' follow-up. Because best corrected visual acuity was 1/400. which respresents a three-line improvement over baseline. which broke through into the vitreous on the following day. This was treated with vitrectomy.Thrombolytic Therapy for Retinal Vein Occlusion 489 years' follow-up. he was not technically eligible for treatment under the protocol for the study. Twenty-one eyes (22%) underwent panretinal photocoagulation for neovasular complications. rhegmatogenous retinal detachment was noted on ultrasound. The . compared with a baseline acuity of 20/400. there was no sign of bleeding during TPA administration. was treated with Institutional Review Board approval under compassionate use circumstances. Anterior segment neovascularization developed in 13 eyes (14%) between 2 months and 1 year after treatment. and intraocular injection of C3 F8 gas. Retinal neovascularization was seen in nine eyes (9%). necrotic-looking retina in the papillomacular bundle. Although the patient remained stable throughout his bleeding episode. Vitreous hemorrhage was noted in 13 eyes (14%). he was treated with intravenous fluids and transfused with several units of blood. In addition to the three patients already described. the fourth patient developed a dense vitreous hemorrhage 4. Her last vision was hand motions. extensive endophotocoagulation. Six weeks later a rhegmatogenous retinal detachment was noted on ultrasound. His last recorded vision was light perception. The patient experienced no sequelae from this episode. Anticoagulation use appeared neither harmful nor beneficial to the TPA-treated patients. the patient denied prior ulcer disease to four different physicians. The bleeding developed 10 hours after completion of TPA administration. One patient experienced mild gastrointestinal bleeding from an undisclosed old ulcer. Interestingly. a 29-year-old man with a 6-day history of profound visual loss. Perfusion status was highly predictive of neovascular complications (Table XI). developed a hemorrhagic sub-RPE detachment superior to the disc. a 70year-old white woman who had had symptoms for 1 month. a superior. On the following day.

a three-line improvement from baseline.490 Elman TABLE XI: DEVELOPMENT OF OCULAR NEOVASCULARIZATION AND PERFUSION STATUS ON BASELINE FLUORESCEIN ANGIOGRAPHIY ISCHEMIC NONISCHEMIC Neovascularization developed No neovascularization *X1 = 8. Baseline 30-Hz implicit times of 40 or greater correlated with the development of ocular neovascularization (Table XII). ERG flicker timing delays had a sensitivity of 83% and a specificity of 94% when a criterion of 7 msec was selected (Fig 2).62. Two patients were excluded from the ERG data analysis because they had a waves only. One eye developed a macular hole 1 year after treatment. ERGs were either recorded at the patient's last visit (patients without iris neovascularization) or just prior to the development of iris neovascularization. Neither had iris neovascularization. TABLE XII: DEVELOPMENT OF OCULAR NEOVASCULARIZATION AND IMPLICIT TIME (IT) ON BASELINE 30-Hz FLICKER ELECTRORETINOGRAPHY (ERG) ERG IT> 40 MSEC ERG IT < 40 MSEC Neovascularization developed No neovascularization 2 8 5 11 62 *X1 = 11. Electroretinograms (ERGs) were analyzed in detail from the first 26 patients observed for at least 6 months. At 6 years' follow-up his vision remains at 5/200.0008 Similarly. p = . this was not repaired surgically. and 18 did not.0033 8 11 7 62 fifth patient required vitrectomy for a vitreous hemorrhage developing 4 months after treatment. .28. p = . ERG scotopic single-flash b-wave timing delays had a sensitivity of 100% and a specificity of 69% when a criterion delay of 6 msec was selected (Fig 1). Six patients developed iris neovascularization.

1988.Thrombolytic Therapy for Retinal Vein Occlusion 491 Figure 3 shows excellent correlation between these two tests. It also demonstrates segregation of the patients who developed iris neovascularization from those that did not. . REPORT OF TWO CASES Case 1 A 68-year-old white woman presented to her referring ophthalmologist on December 21. TPA Study 4- 13 No NV E 3 E~ ~ ~ ~ ~ ~ ~UNV 30 Hz Implicit Tim FIGURE (mec) 2 Flicker timing delays. with a 1-week history of blurred vision in her right TPA Study M0 mm* -- O~ ~ ~ ~ ~ ~ ~ ~CNN O VI 41 47 s0 53 as oS SS 2 BWaV Inplicit Time (meec) FIGURE 1 Scotopic flash b-wave timing delays.

FIGURE 4 Initial appearance of fundus before treatment. Ten days later her vision remained at 20/20. The following week her vision had . F 'f 40 E 4135 40 45 60 S5 s 60 70 B-Wave Impicinlm (iee) FIGURE 3 Excellent correlation between b-wave implicit time and flicker timing delay. although her fundus presentation worsened considerably.492 Elman TPA Study 50 E u . eye. On examination she was found to have a mild CRVO with 20/20 visual acuity (Fig 4).

and her fundus had a classic CRVO appearance. with macular edema. detreiorated to 20/100 while her CRVO continued to worsen in appearance. however. . followed by 10 mg per hour for the remaining 4 hours. Forty milligrams of TPA was infused over the first hour. The following week her vision had improved from 20/320 to 20/64. She was referred to the author 3 weeks after the onset of her symptoms for consideration of thrombolytic therapy. and scattered cottonwool spots.Thrombolytic Therapy for Retinal Vein Occlusion 493 FIGURE 5 Appearance of fundus just before treatment. disc swelling. One aspirin tablet per day was prescribed. both the fluorescein angiogram and electroretinogram showed no evidence of ischemia predictive of anterior segment neovascularization. On the next day she was admitted to the study Clinical Research Center. In the following weeks. vision returned to 20/20. where it remained for 1 year following treatment. dilated tortuous veins. Best corrected visual acuity was 20/320. Medical evaluation detected no contraindication to thrombolytic therapy. Fluorescein angiography showed a delay in filling in the arteriovenous phase. and 20 mg in the second hour. Five weeks following TPA treatment there was dramatic resolution of the CRVO accompanied by further visual return to 20/40 (Fig 6). where she underwent thrombolytic therapy with 100 mg of TPA without complication.

transient ischemic attack. trauma. Fluorescein angiography and electroretinography confirmed the progressive course. when he was seen by his referring ophthalmologist. His vision had deteriorated from 20/20 to 20/32. complaining of a 4. Slitlamp and gonioscopic examinations showed no anterior segment neovascularization or significant abnormality. Case 2 A 59-year-old white man first presented to the author on December 12. peptic ulcer disease.494 Elman ''- g?. melena. and mild hypothyroidism. The patient returned on January 9.1991. thrombolytic therapy was not recommended. 1992.5 in the left eye. Given his apparent improvement. There was no afferent pupillary defect. or other predisposing factors for systemic bleeding. Preadmission best corrected visual acuity was 20/32 in the involved right eye and 20/12. well-controlled hypertension. Confrontation visual fields were full and equal in both eyes. Applanation pressures measured . hematochezia. Vision on that date was 20/40. The patient was in good health. D. and his CRVO had worsened dramatically in comparison with photographs obtained from his first visit. surgery. 1991.i FIGURE 6 Appearance of fundus 5 weeks posttreatment.to 6-week history of decreased vision in his right eye secondary to CRVO. He reported that his vision had started to improve after December 6. he had a 3-year history of adult-onset diabetes mellitus. Review of systems revealed no evidence ofprior cerebrovascular accident.

9%. risks of. Urine was negative for blood. mean corpuscular hemoglobin. His lungs were clear to percussion and auscultation. and TPA was started. At 1:45 PM. and TPA was delayed. The benefits of. and minimal to moderate macular edema. As normally seen in our patients. 20. These were immediately administered. 38 mEq/L. 3. and alternatives to treatment were explained to the patient. immediately after starting the intravenous lines. The ERG and fluorescein angiogram on that occasion showed progression. There was no neovascularization or vitreous hemorrhage. RBCs.6. 6.56 minutes. January 15. His vital signs remained stable throughout the first 4 hours of the infusion. blood pressure was 140/90 and pulse rate 68. cholesterol. 6. but examination showed absolutely no evidence of bleeding orally. 66.Thrombolytic Therapy for Retinal Vein Occlusion 495 10 mm Hg in both eyes. He then informed us that he had not taken all of his blood pressure medications. the patient returned for systemic evaluation by the study protocol cardiologist. and his blood pressure was well controlled (122/68 mm Hg) with medications. 10 mm/hr. There was no recurrence. Sputum was slightly bloodtinged at about 3 PM. Written informed consent was obtained. . Dilated fundus examination of the right eye showed a marked CRVO with intraretinal hemorrhages in all four quadrants of the retina. and whole blood viscosity. The patient desired to proceed with TPA treatment and was admitted that afternoon for administration of the Thrombolysis in Central Vein Occlusion Pilot Study protocol. mean corpuscular volume. sedimentation rate. tortuous venules. The risk of stroke leading to death was explicitly discussed. but the central vein occlusion was still judged as nonischemic. His age was not advanced. prothrombin time was 11. dilated. and partial thromboplastin time was 26 seconds.5 pg. On the morning of admission. disc swelling with blurred margins. At 5 PM. he also had minimal skin oozing from cuts on his hands. all of which were within normal normal limits.9. Blood pressure remained stable. The patient appeared more relaxed in his new hospital setting. 1992. 174 mg/dL. and vital signs remained stable. and all questions were answered. 221 mg/dL. The patient's blood pressure at admission and prior to treatment was within the protocol limits specified. mean corpuscular hemoglobin concentration.9 seconds. the patient's blood pressure was 150/100 and pulse rate was 60 beats per minute. The patient was found to be a low-risk candidate for TPA. random glucose measurement. Laboratory evaluation was normal except for the following minimal abnormalities: CO2 content. Bleeding time was 2. At about 2 PM. 30.6 pm3. globulin. there was no sign of peripheral vascular disease.3. blood pressure was 140/90 and pulse rate was 58. who was familiar with the eligibility and exclusion criteria.

In the MICU. He was alert but in distress. The patient's blood pressure now had increased to 240/140. and he started to vomit. fibrinogen level was 173 mg/dL. the pupils had been pharmacologically dilated at 2 PM at the beginning of TPA administration. the medical intensive care unit (MICU) resident was emergently paged. and his upper and lower limb strength was equal and strong bilaterally. A topical anesthetic drop was administered. TPA was immediately discontinued. the central retinal artery appeared to be closed and the globe tactilely was very hard. effaced sulci. or choroidal effusion. Neurologic consultation was immediately obtained and the patient was evaluated. agitation followed by obtundation. assessment of pupils could not be done. This indicated signs of significantly increased intracranial pressure. vitreous hemorrhage. which has been reported to rarely cause glaucoma. The possibility of a bolt for intracranial pressure monitoring or decompression was discussed with the neurosurgical consultant. He showed no evidence of a facial paresis. The patient was intubated on the clinical research floor. but it failed to relieve the eye pain. Glaucoma could explain the discomfort in the eye. who felt that there was little reason to recommend surgical intervention at this point. The patient was transferred to the MICU for care. although there was no sign of choroidal hemorrhage. through his pharmacologically dilated pupil. With a Schiotz tonometer. The patient continued to vomit over a 15-minute period. and then lethargy. and the patient was then examined. the patient was hyperventilated. and diuretics were administered. and there was no sign of corneal edema. and the nausea and vomiting. Amicar therapy was . Per protocol routine. The working diagnosis at that time was acute glaucoma. One-half hour after TPA was stopped. In retrospect. the pain could also have been due to the cerebrovascular accident that began to evolve clinically over the next 10 to 15 minutes. the pressure in the right eye measured zero scale units. he rapidly developed a left hemiparesis. By indirect ophthalmoscopy. Vision in the right eye was at least counting fingers. A computed tomographic scan of the head showed a large right subcortical/basal ganglia hemorrhage with blood in the ventricles and subarachnoid space.496 Elman At about 5:40 PM. Hematologic consultation was also obtained. while eating dinner. and a nasal gastric tube was placed to prevent aspiration. His speech became slurred. Upon recognition of the elevated blood pressure. and right-to-left early shift with tight cisterns. and prior to the paresis. indicating acute glaucoma. but his pulse remained in the 60s. Therefore. He showed signs of a cushingoid response from elevated intracranial pressure. even in nonthrombolytically treated patients with CRVO. the apparent closure of the central retinal artery. the patient complained of severe eye pain in his right eye.

there was no histopathologic or experimental evidence in the literature to support this contention for CRVO. His blood pressure was maintained with pressor agents. complete clot lysis. A three-line improvement technically cannot be measured in patients with a pretreatment visual acuity better than 20/40. the patient had a cardiac arrest but was resuscitated. time is required before the best outcome can be measured. This is equivalent to improving from 20/80 to 20/25 (Tables V through VII). when his blood pressure suddenly dropped. vision slowly but steadily improved in the group of patients who gained three or more lines vision by their 6-month follow-up visit. there was no significant difference in presenting visual acuity. When eyes presenting with a shorter duration were compared with those presenting with a longer duration. While this was a theoretical consideration.1 lines from the pretreatment level.Thrombolytic Therapy for Retinal Vein Occlusion 497 also started in the MICU. and Mannitol was added. a number of changes in the eye (macular edema. the time when most patients present for evaluation. Intraocular pressure measured 6 mm Hg (normal). The improvement tended to be sustained once achieved. Neurosurgical consultants advised against surgery. subretinal hemorrhage. At about 12 AM. There was concern whether thrombolytic therapy would be effective several weeks after the onset of symptoms. Even with successful. The apparent effectiveness of thrombolytic therapy even . and bradycardiac. Postmortem examination was refused. ten of these patients showed a dramatic and rapid improvement (within weeks) after treatment. However. The slow improvement is not surprising. In the patients who improved by three or more lines. At about 1:30 PM. visual outcome. The data in this study show no reason to believe that patients treated earlier are more likely to improve or regain vision than those treated later. when the right pupil was now noted to be fixed and dilated. intraretinal hemorrhage. and ventricular tachycardia was controlled with medication.1992. The patient remained in stable condition until 8 AM on the following day (January 16). January 17. DISCUSSION The visual acuity results in this study were encouraging. a second neurologic determination was made and the patient was judged to be brain-dead. As a rule. He died at 3:40 AM. ischemia) do not reverse immediately. the average visual acuity gained was 5. The patient was now unresponsive. Fundus examination showed no vitreous. Hyperventilation and diuresis were continued. or choroidal effusion. or complications. As with healing elsewhere in the body. hypertensive.

Standard treatment techniques and data collection methods were developed. The risk of cerebrovascular accident in association with thrombolytic administration is a well-reported. Prospective data from this study were in agreement with the previous findings of Johnson and colleagues. This incidence is consistent with that quoted to our patients in the study informed consent. The definition of ischemia on fluorescein angiography used in this study (areas of nonperfusion. It is impossible to assess whether he sustained an acute eye event that led to an acute rise in blood pressure. where anticoagulation is considered the accepted treatment. the results are all the more striking. Indeed. coumadin is not used after TPA.65 ERG b-wave and 30-Hz flicker implicit time delays were sensitive and specific predictors for the development of iris neovascularization. There were no dosing errors. with only well-controlled hypertension as a potential risk factor.' This study also demonstrated the feasibility of performing a larger randomized trial and the potential efficacy of TPA. precipitating this stroke. although the samples are small. He was enrolled and managed according to protocol. The addition of coumadin does not appear to influence outcome. and validated. This study also validated the reproducibility of the photographic grading system. Furthermore. The regimen of TPA and aspirin is far safer and easier to manage than the coumadin regimen. as evidenced by the one fatality in the study (case 2). expected event. refined. The potential promise of TPA therapy must be soberly balanced with the small but potentially devastating risk of fatal stroke. Experienced graders using a more refined system should achieve the deserved kappas of 0.498 Elman weeks after symptoms commence may relate to the ischemic penumbra in a vascular bed with decreased but not absent blood flow. This was the first cerebrovascular accident encountered in this protocol in the almost 100 patients who had been treated over a 6-year period. This is consistent with previous reports of these characteristics. it is impossible to assess whether the patient had a small aneurysm or an arterovenous malformation that predisposed to .8 or better. Considering that this was the first time either grader used this scheme. with the exception of pulmonary emboli. pruning. Review ofthe findings in case 2 indicated that the patient was at low risk for intracranial hemorrhage. or whether he had an acute bleeding episode that led to the referred eye pain as part of the same event. or black vessels) correlated with the development of ocular neovascularization. The recruitment rate was shown to be compatible with the scope that would be required for a definitive multicenter randomized study. tested.

However.67 Thus. even with visual loss in both eyes. such data would be derived from a randomized. Even when only one eye is involved. TPA is used for clot lysis in limb arterial occlusions. in other branches of medicine. TPA is used routinely for non-life-threatening indications. their reported efficacy. whether per- . absence of randomized controls) precludes definitive recommendations regarding the safety and efficacy of TPA. For these reasons. the author contends that aggressive therapy for CRVO should be considered carefully even when the first eye is involved. in this case they were insufficient to compensate for such a catastrophic event. For example. double-masked clinical trial. Given that the average age in this study was 56 years. should be offered such a therapy. Although the contingency plans to detect and manage such an event performed perfectly as planned. the CRVO eye may ultimately become the better eye. Ideally. and their risks. controlled. The alternative in these cases is bypass surgery or amputation. According to the protocol eligibility and exclusion criteria. he was fully eligible and at low risk. patients complain of disability. His blood pressures. The nursing staff and physicians in charge of monitoring the patient immediately recognized an adverse event and discontinued the TPA.Thrombolytic Therapy for Retinal Vein Occlusion 499 intracranial bleeding. it is the author's clinical practice to actively assist patients in making an intelligent and informed decision regarding their management by thoroughly reviewing all potential treatments. particularly for tasks requiring depth perception. one might question whether patients without a life-threatening disease.and outpatient-based. Informing patients of such treatments does not compel the treating physician to administer those treatments. ophthalmologists may be less accustomed to administering systemic therapy for local diseases than our medical and surgical colleagues. The outcome of untreated CRVO eyes. However. were always within the acceptable limits for this protocol. both before and during treatment. it is the patient's right to know what is available. Informed consent in such a setting is imperative. Given the potential for serious complications and even death. However. The study design in this study (small sample size. elderly patients in the same agegroup as CRVO also have an increased risk of visual loss (about 10%) from exudative age-related macular degeneration. a patient will be best able to participate in his or her care. Given that ophthalmic treatment over the last 20 years has become more procedure. By evaluating the best scientific information extant together with the treating physician's interpretation of those data. Mieler and Blumenkranz20 reported that 25% of fellow eyes presenting with CRVO developed retinal vascular occlusion over a 5-year period.

most studies report just initial and final visual acuity distributions without providing information on change in visual acuity. or who had evidence of ocular neovascularization were excluded. would have been eligible for enrollment in this study. these two groups represent patients who. Unfortunately. Although most of the CVOS patients were enrolled long after 1 month of symptoms. The first group was derived from review of records from all patients presenting to the Wilmer Institute from January 1980 to December 1985 with a diagnosis of CRVO2. All patients had at least 6 months' follow-up. prospective natural history data with uniform follow-up periods and change in visual acuity are unavailable. Furthermore. Short of randomization. Thus. both groups were followed with protocol refractions at an appointed interval with standardized Lighthouse visual acuity charts. which would .500 Elman TABLE XIII: NATURAL OUTCOME OF CENTRAL RETINAL VEIN OCCLUSION CHANGE IN VISION n WILMER INSTITUTE BASCOM PALMER EYE INSTITUTE STREPTOKINASE PLACEBO 104 38 15 Gain of 3 or more lines 14(13%) 2 (5%) 2(13%) Stable within 3 lines Loss of 3 or more lines 55(53%) 16(42%) 4(27%) 35(34%) 20(53%) 9(60%) fused or ischemic. patients from this study who met visual eligibility criteria (20/50 to 20/200) for the Central Vein Occlusion Study (CVOS) were compared with patients in the CVOS at 1 year after enrollment. Patients who were older than 75 years. The third group illustrates those patients assigned to placebo in the streptokinase study with initial vision of 20/400 or better. The second group comes from review patients identified from the fluorescein angiography records of the Bascom Palmer Eye lnstitute. is regarded as poor. In Table IX.20 In both groups. in contrast to this study. patients were selected on the basis of an unambiguous CRVO. on the basis of the best available information. who had entrance vision less than 20/800. Table XIII shows the best natural outcome data available for comparison. documented by fundus photography and fluorescein angiography.

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