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Vascular and Interventional Radiology |
1 From the Departments of Neuroradiology and Therapeutic Angiography (J.N.V., A.A., D.H., J.J.M.), Ophthalmology (P.M., M.P., P.Y.S., A.G.), and Anesthesiology and Critical Care Medicine (M.R.L.), Hôpital Lariboisière, Paris, France. Received May 26, 1999; revision requested July 19; revision received November 2; accepted November 12. Address correspondence to J.N.V., Charcot Diagnostic and Interventional Neuroradiology Service, Groupe Hôpitalo-Universitaire Pitié-Salpétrière, 47-83 boulevard de l'Hôpital, 75651 Paris cedex 13, France.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Thirteen patients had recent severe nonischemic CRVO for which no alternative therapy was available. A flow-guide microcatheter was introduced coaxially via the femoral artery into the ophthalmic arterial ostium, and urokinase was perfused for 40 minutes. Vision, funduscopic findings, and retinal perfusion were assessed during 1 year of follow-up.
RESULTS: Five of the 13 patients treated experienced visual improvement (P = .05) and retinal perfusion within 24–48 hours. Vision returned to normal within 24–48 hours in three patients, within 1 week in one patient, and within 1 month in one patient. These five patients exhibited progressive lesion regression within 2–4 weeks at funduscopy. Their clinical course prior to treatment resembled that of combined central retinal arterial occlusion (CRAO) and CRVO, which typically has a poor visual outcome. One patient relapsed 1 month after fibrinolysis. Of the remaining eight patients, one had normal vision at 12 months, and seven had no improvement. No technical complications were observed.
CONCLUSION: Although there was no control group, the short period between fibrinolysis and substantial visual improvement, combined with marked retinal perfusion improvement, suggests that fibrinolysis is beneficial for CRVO, especially for recent CRAO and CRVO.
Index terms: Eye, abnormalities, 1724.124, 1724.1265, 1724.752, 2245.124, 2245.89 • Retina, 17.75, 2245.1265, 2245.129, 2245.89 • Urokinase, 1724.1265, 2245.1265
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The treatment of CRVO remains controversial and disappointing overall. To our knowledge, different therapies, including continuous intravenous systemic heparin administration, intravenous systemic fibrinolysis, orally administered antiplatelet aggregates, orally administered anti–red blood cell aggregates, corticosteroids, isovolumic hemodilution, hyperbaric oxygen, and intravitreal fibrinolysis, have not proved effective (9–16).
Today, the technical possibilities afforded by interventional neuroradiology allow atraumatic, safe, selective microcatheterization of the intracerebral vessels and have opened the way to new therapies. Our procedure was based on an original approach to the treatment of venous thrombosis through a superselective arterial route for the administration of a fibrinolytic agent as close as possible to the occlusion to obtain a high local concentration of fibrinolytic activity and to avoid systemic side effects. The purpose of our study was to determine the effect of selective local urokinase perfusion into the ophthalmic artery as a treatment for CRVO, which otherwise would have a poor outcome.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The patients in the study were examined during normal or emergency ophthalmologic consultations in our department of ophthalmology and were found to have CRVO. The diagnosis of CRVO was established by two ophthalmologists in consensus (P.M., M.P., P.Y.S., or A.G.) in accordance with the following criteria: (a) having various degrees of unilateral visual loss at visual acuity measurement and (b) having dilated tortuous retinal veins in four quadrants and scattered panretinal hemorrhages at funduscopic examination.
Each patient initially had undergone a complete ophthalmologic workup, which included ophthalmologic history, Snellen visual acuity with best correction, applanation tonometry, ophthalmoscopy, slit-lamp biomicroscopy of the anterior and posterior segments of eye, and fluorescein angiography.
The patients included in this prospective study experienced severe unilateral visual loss less than 30 days before presentation, with visual acuity of less than 20/100; an abnormally long retinal arteriovenous transit time, exceeding 10 seconds between emergence of the dye in the central retinal artery and the appearance of venous laminar flow at the optic disk at intravenous fluorescein angiography; a previous episode in the other eye, with worse visual outcome; and/or a previous episode in the same eye, with secondary improvement. Patients underwent no other treatment before fibrinolysis.
Patients with extensive ischemic CRVO (7) were excluded for fear of increasing the abundant retinal hemorrhages usually present in the ischemic forms and to avoid potential hemorrhagic transformation of the ischemic infarction due to sudden revascularization after thrombolysis. Being pregnant, having a known severe blood coagulation disorder, or having urokinase intolerance were additional exclusion criteria.
All patients selected for fibrinolysis received complete information about this therapy. After we obtained their informed consent, patients were referred to our institution's interventional neuroradiology department.
Treatment
All patients underwent a standard preoperative physical examination and a laboratory work-up. Fibrinolysis then was performed in the angiography room with the patient under neuroleptanalgesia (25 µg/kg/h midazolam hydrochloride [Hypnovel; Roche, Neuilly-sur-Seine, France] and 20 µg/kg/h alfentanil [Rapifen; Janssen, Boulogne-Billancourt, France]). To prevent thrombosis due to the presence of catheter systems, systemic heparin sodium (Heparin Choay; Sanofi-Synthelabo, Le Plessis-Robinson, France) was administered initially as an intravenous bolus of 50 IU per kilogram of body weight to maintain an activated partial thromboplastin time of at least twice the normal time throughout the procedure.
With the patient under local anesthesia, the internal carotid artery was catheterized via the femoral artery with a 5-F vertebral guide catheter (Glide) and with a 0.035-inch hydrophilic polymer-coated guide wire (Radifocus; both from Terumo, Tokyo, Japan) by using fluoroscopy and, when necessary, a display of the wall of the vessels (the vascular tree, or "road map") at maximum opacification without anatomic background. An initial internal carotid cerebral arteriogram (lateral view) then was obtained with a nonionic contrast medium (iohexol [Omnipaque 300; Nycomed, Oslo, Norway]) as a reference (Fig 1). Review of the arteriograms allowed us, by using steam, to give an S shape to the tip of the microcatheter, in accordance with the geometry of the carotid arterial siphon and the ophthalmic arterial ostium. A 1.8- or 1.5-F flow-guide microcatheter (Magic, Balt Extrusion, Montmorency, France, or Spinnaker, Target/Boston Scientific, Fremont, Calif) was advanced coaxially into the ophthalmic arterial ostium and through the guide catheter with fluoroscopic guidance.
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Superselective ophthalmic arteriography was performed to check the patency of the different branches of the ophthalmic artery and to check for choroidal blush (Fig 2). It did not reveal any arterial or venous abnormalities, and the retinal arteries and veins were not distinguishable from the choroidal arteries and veins.
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After fibrinolysis, all patients were infused continuously with 30 IU/kg/h heparin to maintain an activated partial thromboplastin time of at least twice the normal level for the next 48 hours. Patients were discharged after 72 hours of hospitalization with a prescription for 5,000 IU of subcutaneous low-molecular-weight heparin (tedelparine [Fragmine; Pharmacia France, St Quentin-Yvelynes, France]) per day for 1 month and with a prescription for 250 mg per day of oral aspirin for 3 months.
Follow-up and Assessment of Outcome
The examinations performed were (a) Snellen visual acuity test with best correction for distance by using an 18-line logarithmic table; (b) funduscopic examination to evaluate hemorrhage, retinal and papillary edema, venous and arterial calibers, and the overall quality of the capillary bed, with the amount of intraretinal blood classified as small, moderate, or abundant; and (c) intravenous fluorescein angiography to estimate retinal circulation, which was evaluated by using the retinal arteriovenous transit time (normal, 
2 seconds). This was defined as the time in seconds between the first appearance of the dye at the origin of the central retinal artery and the first laminar flow in any of the retinal veins that received peripheral blood at the edge of the disk.
Patients were examined by two ophthalmologists in consensus (P.M., M.P., P.Y.S., or A.G.) before fibrinolysis, 24–48 hours thereafter, and during follow-up at 7, 15, 30, 90, and 180 days and at 1 year.
Statistical Analysis
In view of the small number of patients, the mean evolutionary trend for vision was tested with multiple comparisons of mean paired visual acuity measurements made during treatment and follow-up. The Student t test for paired values with the Bonferroni correction and with a significance level of .05 was used to account for the multiple comparisons.
Correlations between visual outcome and baseline characteristics (patient age, visual loss features, duration of symptoms prior to fibrinolysis, retinal posterior pole features, retinal hemorrhages, retinal arteriovenous transit time, and visual acuity) were evaluated by using the Spearman rank correlation exact test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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20/100) at presentation; eight (62%), an abnormally long retinal arteriovenous transit time (>10 seconds). Five (38%) patients had ischemic whitening of the retinal posterior pole and delayed central retinal arterial filling (Fig 3); one (8%) had retinal whitening along a cilioretinal artery of the temporal pole, with prolonged filling of the cilioretinal artery. At presentation, the visual acuity of the 13 patients ranged from counting fingers at 3 feet (90 cm) (<5/200) to 20/40 (mean, 20/100; median, 20/100), and the mean retinal arteriovenous transit time was 14.4 seconds (range, 2.0–25.7 seconds). All 13 patients were examined at 1, 7, 15, 30, and 90 days after fibrinolysis; 12 were examined at 6 months; and 10 were examined at 1 year.
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Statistical Results
Mean visual improvement 24–48 hours and 30 days after fibrinolysis was significant, according to results of the Student t test for paired visual acuity measurements obtained before fibrinolysis and at 24–48 hours and 30 days. The P value for comparison of paired measurements obtained before and 24–48 hours after fibrinolysis was .025; the P value for comparison of paired measurements obtained before and 30 days after fibrinolysis was .008. When the Bonferroni correction was applied, the P value of paired visual acuity measurements obtained before and 24–48 hours after fibrinolysis was .050 (2 x .025); the P value of paired visual acuity measurements obtained before and 30 days after fibrinolysis was .016 (2 x .008); mean visual improvement still was significant at 24–48 hours and at 30 days after fibrinolysis. Results of the Spearman rank correlation exact test showed that at 24–48 hours, the better the initial visual acuity, the better the visual outcome, with a Spearman 
coefficient of 0.571 and with a P value of .048.
Patients' baseline characteristics, which included the time from visual loss onset to treatment, did not correlate with the visual outcome, except for whitening of the retinal posterior pole (Spearman coefficients were 0.780 and 0.863 at 24–48 hours and at 30 days after fibrinolysis, respectively, with corresponding P values of .007 and .003).
The baseline characteristics of the subgroup of patients with improvement shortly after fibrinolysis versus the subgroup of patients without improvement were (a) a lower mean age (range, 42–69 years) of 52.0 years (median, 52.0 years; mean of 62.0 years and median of 58.5 years in the patients without improvement); (b) sudden onset of initial visual loss in all five patients with improvement but in only three of the eight patients without improvement; (c) a lower mean duration of symptoms prior to fibrinolysis (range, 0.5–10.0 days; mean, 3.7 days; median, 3.0 days; mean of 14.2 days and median of 15.0 days in the patients without improvement); (d) very few retinal hemorrhages in four of the five patients with improvement versus moderate or abundant hemorrhage in the patients without improvement; (e) ischemic whitening of the retinal posterior pole in all patients with improvement versus no whitening of the retinal posterior pole in the patients without improvement; and (f) prolonged retinal arterial filling, as indicated by a very long retinal arteriovenous transit time (range, 10.0–25.7 seconds; mean, 20.5 seconds; median, 23.0 seconds; mean of 10.6 seconds and median of 9.6 seconds in the patients without improvement).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In that study (7), initial visual acuity was an important predictor of the final visual prognosis. When it was 20/50-20/200, only 58 (19.1%) of 304 eyes improved to greater than 20/50, and 113 (37.2%) of 304 deteriorated to less than 20/200. When initial visual acuity was less than 20/200, three (1.5%) of 201 eyes improved to greater than 20/40, and 159 (79.1%) of 201 remained at less than 20/200, whether or not they initially were nonischemic. Any improvements occurred during the 1st year of follow-up. After 4 months of follow-up, 81 (15%) of 547 of initially nonischemic eyes developed ischemia; after 3 years, 185 (34%) of 547. The main predictors of complications were visual acuity and the amount of capillary nonperfusion. Iris and/or angle neovascularization affected 117 (16.4%) of 714 eyes, including 58 (10.8%) of 538 of the initially nonischemic eyes (7). Quinlan et al (6), who reviewed the natural course of CRVO in 168 eyes, noted macular pigment changes that resulted from chronic cystoid macular edema in 79 (73.8%) of 107 nonischemic eyes.
Thrombosis as the cause of CRVO is controversial. Nevertheless, Green et al (5) established that thrombosis of the central retinal vein at the level of the lamina cribrosa retrolaminar optic nerve was a constant histopathologic finding in all of the 29 eyes reported in their study to have CRVO. A thrombus was observed, with or without recanalization, in histopathologic sections of recent or old CRVO at the site where the artery and vein share a common adventitia. At this site, sclerotic changes in the arterial wall may mechanically compress the accompanying vein, narrow its lumen, and slow down the blood flow, which sometimes results in thrombosis. At histopathologic examination, such thrombi were similar in composition and origin to other venous thrombi throughout the body.
Although the initial pathophysiologic conditions of CRVO are controversial, they probably are caused by a complex combination of mechanisms, which include altered blood flow, altered blood viscosity, abnormalities of hemostasis, degenerative vessel wall changes, and an abnormal perivascular status (1–4,17–21). The consequent sluggish venous flow probably is the cause of thrombus formation, which leads to venous occlusion. It might explain the transition from hemodynamically tolerated venous caliber reduction to venous occlusion with hemodynamic and clinical decompensation (22).
A rare condition of CRVO has been described in the literature (23–28). CRVO is combined with sudden visual loss and with ischemic whitening of the retinal posterior pole at fundal examination and prolonged retinal arterial filling at fluorescein angiography, which reveals combined central retinal arterial and venous obstruction (CRAO and CRVO). Five of the patients in our series (patients 1–5) had similar findings at presentation prior to treatment. The visual outcome of this condition typically is poor; thus, all 15 cases of combined CRAO and CRVO reported by Brown et al (27) were accompanied by severe visual loss, although investigators in another article (24) reported improved vision in two such cases. It is unfortunate that to our knowledge no effective treatment to reverse the visual loss is available. The underlying mechanism of the initial combination of CRAO and CRVO remains to be identified (29,30).
In the presence of CRVO, obstruction of the cilioretinal arteries includes clinical features of CRVO, with retinal whitening along the obstructed artery at fundal examination and with either normal filling or, in the presence of a more severe form of CRVO (in patient 10), delayed filling of the cilioretinal artery at fluorescein angiography (31,32). The pathogenesis of CRVO associated with cilioretinal arterial occlusion still is unclear, and its natural history, which generally has a favorable long-term outcome, depends on the severity of the venous obstruction (33).
The treatment of CRVO is controversial, and to our knowledge no controlled trial yet has proved clearly beneficial (9–13). Systemic heparin, alone or combined with aspirin, brought no visual improvement in two studies (10,11). In a randomized series of 40 patients with CRVO, streptokinase (600,000 IU) followed by anticoagulants, versus no treatment, improved visual outcome slightly but caused vitreous hemorrhage with blindness in three (15%) of 20 patients (12).
Elman (13) treated patients with CRVO with intravenous tissue plasminogen activator plus aspirin. At 6-month follow-up, 37 (42%) of 89 eyes had gained at least three lines of vision, and 19 (21%) of 89 had lost at least three lines. Most patients improved slowly. The duration of symptoms before treatment did not affect visual outcome. The absence of randomization prevented any conclusion from being reached with regard to the safety and effectiveness of tissue plasminogen activator. Nevertheless, this treatment seems promising but carries small risks of intraocular or gastrointestinal bleeding and of fatal stroke in patients without life-threatening disease. Treatment with intravitreal fibrinolysis by using recombinant tissue-type plasminogen activator (14) appeared beneficial in seven (30%) of 23 eyes with CRVO without drastic hemorrhage but may worsen vision in some.
Local intraarterial thrombolysis allows the use of a high local concentration of thrombolytic agents, with less systemic effect than intravenous thrombolysis. However, as fibrinolysis does not prevent new thrombus formation, clot dissolution requires a combination of two agents: (a) an anticoagulant such as heparin to inhibit coagulation on the thrombus and to limit clot extension and recurrence and (b) an antiplatelet aggregation agent such as aspirin to combat risk factors for atherosclerosis and to prevent further thrombosis. The beneficial effects of this combination have been documented in patients with cardiovascular or cerebrovascular disease (34).
In our study, all patients had initial clinical features that indicated that without fibrinolysis their visual outcomes would have been poor, as no alternative therapy was available. At initial examination, the five patients treated successfully had symptoms of combined CRAO and CRVO. These patients had no capillary closure, as proved with the persistence of perfused capillaries at fluorescein angiography, and four of them had no macular edema; this suggests that the impairment of retinal arterial perfusion was responsible for their visual loss. Fluorescein angiography was very helpful for distinguishing retinal ischemia due to significant retinal capillary obliteration in ischemic CRVO alone or in CRAO alone from retinal ischemia due to the extreme slowing of retinal arterial perfusion with no retinal capillary obliteration in combined CRAO and CRVO. However, one patient (patient 5) had macular edema at presentation that may have been a cause of visual loss with short-term vision fluctuation. In accordance with the time required for urokinase to act, the short period between fibrinolysis and substantial mean visual improvement, combined with marked improvement of retinal perfusion, suggests that fibrinolysis is beneficial. In patient 5, the beneficial effect of fibrinolysis was less clear, but angiographic features nevertheless improved markedly.
There were no complications due to fibrinolysis except for a slight transient increase in hemorrhages observed after fibrinolysis in all five patients who improved; it is possible that this was due to the sudden restoration of arterial circulation in the presence of venous obstruction, as reported in the experimental work of Hayreh et al (30). Since our group of patients was small and no control group was available for comparison, no conclusions can be drawn regarding the effectiveness and safety of superselective fibrinolysis in patients with combined CRAO and CRVO.
A little more than 1 month after fibrinolysis, one patient in our series (patient 5) had a recurrence of CRVO, with visual loss that worsened to 20/50. This occurred after the discontinuation of low-molecular-weight heparin administration, although aspirin administration had been maintained. A few weeks after the discontinuation of aspirin at 3 months, visual acuity decreased again to 20/200. With no further treatment, this patient developed cystoid macular edema and, at the last follow-up, visual acuity was 20/200. This case raised the questions of whether to perform a second fibrinolysis after recurrence and of what the duration of treatment designed to prevent recurrence should be.
One of the remaining eight patients (patient 10), who had CRVO associated with cilioretinal arterial occlusion, exhibited normalization of visual acuity and of the fundus within 12 months in accordance with the natural history of this disorder. Among the patients without improvement, fibrinolysis was not shown to have any effect on the occurrence of complications that involved macular edema or retinal ischemia. We believe that the treatment failures might have been due to our methods, in which the local concentration of fibrinolytic agent may have been too low or maintained too briefly. Our technique of superselective ophthalmic arterial fibrinolysis was based on that of local intraarterial thrombolysis in the middle cerebral territory (35). The administration rate and dose of fibrinolytic agent were reduced in relation to the ophthalmic arterial caliber and to its corresponding territory of perfusion.
In conclusion, these preliminary results in a small series of patients show that, in certain patients with CRVO, a marked improvement of vision and retinal perfusion occur shortly after minimally invasive local intraarterial fibrinolysis and suggest that fibrinolysis may have a rapid beneficial effect and may cause less systemic disturbance than intravenous thrombolysis, especially in patients with recent combined CRAO and CRVO. In the future, CRVO will be the subject of controlled studies designed to evaluate all the factors involved in the therapy described here.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, J.N.V., J.J.M., A.G., M.P., P.M., P.Y.S.; study concepts and design, J.N.V., J.J.M., A.G., M.P., P.M., P.Y.S.; definition of intellectual content, J.N.V., J.J.M., A.G., M.P., P.M., P.Y.S.; literature research, all authors; clinical studies, all authors; data acquisition and analysis, all authors; statistical analysis, J.N.V.; manuscript preparation, editing, and review, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  H Shahid, P Hossain, and W M Amoaku The management of retinal vein occlusion: is interventional ophthalmology the way forward? Br. J. Ophthalmol., May 1, 2006; 90(5): 627 - 639. [Abstract] [Full Text] [PDF]
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J.-N. Vallee, M. Paques, A. Aymard, P. Massin, P.-Y. Santiago, P. Adeleine, A. Gaudric, and J.-J. Merland Combined Central Retinal Arterial and Venous Obstruction: Emergency Ophthalmic Arterial Fibrinolysis Radiology, May 1, 2002; 223(2): 351 - 359. [Abstract] [Full Text] [PDF]
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