The purpose of this study was to determine the efficacy and safety of selective intra-arterial thrombolysis in patients with central retinal artery occlusion (CRAO).
Medical records for 44 eyes of 44 patients diagnosed with acute non-arteritic CRAO and thrombolysis between October 2010 and February 2019 were analyzed retrospectively. Based on visual acuity, fundoscopic findings, and fluorescein angiography, the patients were classified into three stages: incomplete, subtotal, and total. The perfusion state using the best-corrected visual acuity (BCVA), arm to retina time, and arteriovenous passage times, after 1 month, 6 months, and at the final visit after the procedure, were compared with baseline readings.
Improvement of visual acuity was confirmed in 31 out of 44 patients (70.45%). The mean BCVA of 44 patients changed from 1.65 ± 0.78 logarithmic minimum angle of resolution (logMAR) at the first visit to 1.18 ± 0.91 logMAR at the last visit (
Selective intra-arterial thrombolysis can be helpful in patients with subtotal CRAO in terms of visual improvement and retinal arterial reperfusion.
Central retinal artery occlusion (CRAO) is an ophthalmic emergency caused by the interruption of blood supply to the inner layer of the retina, subsequently leading to a sudden painless loss of vision [
CRAO, the ocular analog of cerebral ischemic stroke, arises due to the occlusion of the central retinal artery (CRA) [
The European Assessment Group for Lysis in the Eye (EAGLE) trial, a prospective, randomized, and multicenter study, compared the effects of IAT with that of the standard conservative therapy. There were no significant differences between the final best-corrected visual acuity (BCVA) of the two therapies, although there were adverse reactions that occurred more frequently in the IAT group. Therefore, IAT was not recommended for the treatment of CRAO [
CRAO can be divided into three stages based on visual acuity (VA), fundoscopic findings, and fluorescein angiography (FA), which helps determine its prognosis. Incomplete CRAO shows a decrease in VA, mild retinal edema, a slightly macular cherry-red spot, and a mildly delayed flow in FA. Subtotal CRAO shows a severe decrease in VA and macular cherry-red spot with marked retinal edema and a significant flow decrease in FA. Total CRAO shows massive retinal edema, with VA dropping to no light perception, along with choroidal hypoperfusion and, in some instances, no cherry-red spot [
Therefore, to evaluate the efficacy and safety of selective IAT, we retrospectively studied patients who were classified into groups according to their CRAO stage based on test results. We then compared BCVA and evaluated the change in the retinal perfusion state by using FA. Furthermore, we noted the adverse reactions of IAT.
This study retrospectively analyzed the medical records of patients who were diagnosed with acute non-arteritic CRAO and underwent thrombolysis at the neurosurgery or radiology department, after visiting ophthalmology outpatient and the emergency department, from October 2010 to February 2019. This study was approved by the institutional review board of Wonkwang University Hospital (WKUH 2020-04-025-001) and complied with the Declaration of Helsinki. Informed consent was waived due to the retrospective nature of the study using medical records.
Participants of the study included those diagnosed with non-arteritic CRAO and could be followed up for at least 6 months. A total of 44 eyes from 44 patients (31 males, 13 females; mean age, 67.00 ± 12.43 years; age range, 46–89 years) were included in this study. The baseline characteristics and exclusion criteria for the participating patients are outlined in
The following information was collected, while medical and ophthalmic examinations were conducted on all patients during their visit to the outpatient and the emergency department: (1) past medical history of conditions such as hypertension, diabetes, hyperlipidemia, cerebrovascular disease, and cardiovascular disease; (2) the time taken from symptom onset to the hospital visit; (3) BCVA using the Snellen chart; (4) intraocular pressure; (5) fundus examination; (6) spectral-domain optical coherence tomography (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany), and 7) FA (Spectralis HRA2, Heidelberg Engineering).
An adequate explanation was provided to the patient and guardian regarding the necessity, procedural method, side effects, and precautions for thrombolysis. After consent was obtained, thrombolysis was performed at the neurosurgery or radiology department of the hospital. The time taken from the onset of symptoms until the procedure was noted.
In addition, the patients were assessed for any complications that occurred either after the examinations at the time of visit or after the procedure, excluding for OCT; or at their visit 1 month after the procedure; or at their final visit 6 months after the procedure.
The procedure was performed as follows: a 6 Fr sheath was inserted through a puncture in the femoral artery, while a 6 Fr (or 5 Fr) catheter was used to access the common carotid artery and cerebral blood vessels. The ophthalmic artery flow was confirmed through an internal carotid artery (ICA) angiogram, while the ophthalmic artery orifice was observed with an oblique lateral angiogram. This was followed by a confirmation of the collateral ophthalmic artery flow and the occlusion site through an external carotid artery angiogram. After a precise selection of ophthalmic artery using a microwire and catheter, 300,000 units of urokinase (UK) (Grenn Cross, Yongin, Korea) were infused into the artery. If the ophthalmic artery was visible at this stage, the drug was injected into the lesion, and if a precise selection was not possible, the drug was injected near the entrance of the ophthalmic artery. Finally, we observed the change in ophthalmic artery flow using the ICA angiogram. After completion of the procedure, 100 mg of aspirin (Astrix; Boryung, Seoul, Korea) was administered for maintenance therapy.
First, the patient group was classified into three stages (incomplete, subtotal, total) based on VA, fundoscopic findings, and FA. The VA was measured using the Snellen chart and converted to logarithmic minimum angle of resolution (logMAR) measurement for statistical analysis at a later stage. Low VAs that were obtainable through measures such as counting fingers or hand motion was converted to logMAR measurements by the method proposed by Lange et al. [
Arm-to-retina time (ART) and arteriovenous passage time (AVP) were measured using FA to identify the problem of perfusion as well as the CRAO stage. After IAT, if ART and AVP showed a decrease of more than 20%, compared to the readings at the time of the first visit, CRAO was considered to have achieved reperfusion.
For data analysis, PASW Statistics ver. 18 (SPSS Inc., Chicago, IL, USA) was used. This study had a small number of participants. Therefore, to examine the normality of the distributions of the participating groups, the comparison between the two groups, which showed normality according to the results of a Kolmogorov-Smirnov’s normality test, was tested using the independent
VA improvement was confirmed in 31 of 44 patients (70.45%). The mean BCVA of the 44 patients was 1.65 ± 0.78 logMAR at the first visit, 1.375 ± 0.91 logMAR (
Significant VA improvements of at least 0.3 logMAR were noted in 17 out of 44 patients (38.64%). VA improvement was less than 0.3 logMAR in three patients (6.82%), while 24 patients (54.55%) experienced no improvement. When examining results by stages, a VA improvement of less than 0.3 logMAR was found in two out of five patients (40%) at the incomplete stage, and the remaining three patients (60%) did not show an improved VA. Moreover, at the subtotal stage, 17 out of 34 patients (50%) showed significant improvements, one patient (2.94%) showed an improvement of less than 0.3 logMAR, and 16 patients (47.06%) experienced none. However, in the total stage, all five patients (100%) did not show any improvement (
Perfusion recovery was observed in 40 (90.91%) out of the 44 patients. Recovery was observed in 100% of those in the incomplete stage, 91.18% in the subtotal stage, and 80% in the total stage (
Following IAT, two patients (4.55%) developed intracranial hemorrhage, a serious complication. Both were admitted to the neurosurgery clinic of our hospital and underwent the Burr-hole drainage procedure. One of the patients was discharged in a mentally alert state, and the other underwent drainage surgery due to the occurrence of intracranial hemorrhage 8 days after the procedure. However, the guardian of the second patient did not wish for active treatment after the operation and, therefore, the patient died due to a Do-Not-Resuscitate order. Another patient (2.27%) had a reoccurrence of CRAO in the same eye within 217 days after the procedure, and IAT was administered once more. Initially, this patient was admitted to the hospital with an ART of 36 seconds in the ‘VA hand motion’ during the first visit, which improved to 12 seconds of ART in the ‘VA counting fingers’ during the last visit following IAT. The patient complained of decreased VA again after 217 days in the same eye and was diagnosed with a relapse of CRAO after an examination. VA hand motion and ART were measured and found to be 60 seconds. Therefore, IAT was performed again, where VA counting fingers and ART improved to 16 seconds. Furthermore, dizziness occurred in nine patients (20.45%), and headache in eight (18.18%), which included the three patients with dizziness. Two patients (4.55%) complained of systemic itching that improved after intramuscular injection of chlorpheniramine maleate 2 mL (Peniramine; Yuhan, Seoul, Korea) and dexamethasone 5 mL (Dexamethasone; Bukwang, Seoul, Korea). The itch was considered to be a side effect of the contrast. One of these patients (2.27%) complained of eye pain, and an ophthalmic examination determined that it was not due to an increase in intraocular pressure. Hand tremors occurred in two patients (4.55%) (
There has been no treatment established for the management of CRAO, and the use of IAT has been a subject of debate due to the paucity of large-scale clinical trials in this regard. The EAGLE trial had shown similar outcomes for IAT compared to conservative treatments but did not recommend it owing to the high rate of adverse effects [
CRA is a branch of the ophthalmic artery that originates from the ICA, and occlusion of the CRA or the ophthalmic artery can be considered as an ocular analog of stroke among ICA occlusions [
To evaluate the degree of perfusion, ART and AVP can be measured [
In this study, we divided the patients into three stages based on VA, fundus findings, and FA to determine the efficacy and prognosis of IAT in CRAO. There was a statistically significant difference in baseline BCVA during patient classification (
Out of a total of 44 patients, IAT was performed in five patients at the incomplete stage (11.36%), 34 at the subtotal (77.28%), and five at the total (11.36%). Furthermore, VA improved in 31 patients (70.45%), of whom six (13.64%) from the subtotal stage showed significant improvement. Anatomical reperfusion was confirmed in 42 patients (95.45%). Schmidt and Schumacher. [
Thrombolytics are recommended for administration within 4.5 hours of stroke onset [
Moreover, a part of the retinal flow remains when CRAO occurs in humans. In the case of an incomplete stage, there is a possibility to observe improvements in the collateral circulation, which results in longer resistance to ischemia. In addition, active treatments such as IAT could help restore the blood supply in the retina, as they have a wider therapeutic window. However, they are less effective in situations such as total occlusion or pronounced hypoperfusion of the choroid [
In the current study, there was a statistically significant difference in the degree of VA improvement between each of the patient groups that underwent IAT (
There also was a significant difference in the degree of VA improvement between the incomplete stage and the subtotal stage (
This may be due to a good initial VA reading for the incomplete stage, which did not show significant improvement even after treatment. However, in the subtotal stage, the initial VA was poor but had significantly improved due to treatment and, ultimately, showed the highest proportion of VA improvement among the groups. Furthermore, the absence of VA improvement in the total stage, which showed no differences during comparisons, was also considered to have contributed to such results.
Regardless of the CRAO stage, the 29 patients (n1) who visited the hospital with referrals and received treatment at the outpatient clinic, as well as 14 patients who had visited the emergency department for treatment (n2) (total = 43, one patient was excluded as the they experienced a relapse of CRAO), had significant differences at the time of visit between two groups (n1 = 19.810 hours, n2 = 4.071 hours,
However, there was no statistically significant difference between the two groups based on the time of the visit and the criteria for improvement of VA outlined in this study (
In this study, we injected the UK into the superselected ophthalmic artery (n = 36). However, when there was no possible selection, UK was injected near the entrance of the ophthalmic artery (n = 8). There was no significant effect on the prognosis after treatment between these two groups. Selective IAT acts locally on the blocked artery, compared to systemic thrombolysis, and reduces systemic exposure, allowing smaller amounts to be used. However, it may cause intracranial or intraretinal hemorrhage, transient ischemic attack, and other neurological symptoms [
The probability of VA recovery following conservative treatment for CRAO is approximately 1% to 15% [
There are a few limitations to our study. First, our retrospective study was performed on all patients except for those who refused to undergo therapy or in those who had received anti-platelet therapy (four patients). Since neither the patients were recruited nor were they examined to write a thesis. Therefore, a control group was not included because follow-up would have been not possible or, even if it were possible, could not be conducted consistently. Accordingly, there are also limitations while comparing and predicting the progress, prognosis, and risks associated with IAT treatment. Since the therapeutic window was wide (up to 74.5 hours), the possibility that retinal ischemia had already occurred cannot be dismissed. This is due to the policy of Korea’s tertiary hospitals requiring referrals for outpatient treatment but not requiring this when the patient visits through the emergency department. Second, we did not include a limit for BCVA while selecting patient groups. Therefore, patients with good VA were also included, which may have affected the baseline values and the analysis of IAT results. This was done because all the 44 patients, except for one who had a relapse of CRAO, experienced their first visit to the emergency department or underwent treatment at the outpatient department. Moreover, the cilioretinal artery, which is a branch of the posterior ciliary artery, is present in 32% to 50% of people [
Furthermore, when the types were subdivided in a table (
CRAO has a low prevalence (1–1.4 per 100,000 people) and the fact that patients see objects with both eyes might delay symptom recognition. There is also a possibility that hospitalization could be delayed due to the patient’s assumption that there will be an improvement after a sudden decrease in VA. Therefore, educating the community regarding these abnormalities as well as stroke symptoms is necessary to instill in people the importance of recognition of the sudden decrease in vision, prompting them to visit an emergency department or a nearby ophthalmology clinic for treatment.
Besides, proper education about the need for regular ophthalmic examination and addressing modifiable risk factors, such as metabolic syndrome, lifestyle, alcohol, and smoking, are necessary for people with at-risk conditions such as hypertension, diabetes, and hyperlipidemia.
In conclusion, CRAO is an ocular emergency that could lead to loss of vision; therefore, other systemic ischemic events must also be considered. In addition to CRA reperfusion, ocular complications and systemic vascular ischemia must also be managed together. In the current study, IAT was effective in improving VA in the subtotal stage of CRAO and was effective for reperfusion in all the stages. Therefore, IAT should be used to treat CRAO with sufficient consideration of the risks and benefits. A better randomized controlled trial will be needed in the future to demonstrate the universally safe and effective use of IAT.
This study was supported by Wonkwang University in 2020.
No potential conflict of interest relevant to this article was reported.
The initial optical coherence tomography of three central retinal artery occlusion (CRAO) subtype group. (A) Incomplete CRAO, (B) subtotal CRAO, and (C) total CRAO.
Comprehensive changes in visual acuity after intra-arterial thrombolysis (IAT) in central retinal artery occlusion patients. (A) Mean logarithmic minimum angle of resolution (logMAR) visual acuity after IAT treatment according to stage of central retinal artery occlusion. (B) Changes in the Final logMAR visual acuity according to stage of central retinal artery occlusion. BCVA = best-corrected visual acuity. *Statistically significance is
Baseline characteristics of 44 patients who underwent intra-arterial thrombolysis for CRAO
Variable | Data (all) | Incomplete CRAO | Subtotal CRAO | Total CRAO | |
---|---|---|---|---|---|
Total (eye, %) | 44 | 5 (11.36) | 34 (77.28) | 5 (11.36) | 0.296 |
Male | 31 (70.45) | 5 | 23 | 3 | |
Female | 13 (29.55) | 0 | 11 | 2 | |
Age (yr) | |||||
Mean ± SD | 67.00 ± 12.43 | 56.00 ± 1.42 | 67.47 ± 12.31 | 74.80 ± 2.43 | 0.069 |
Range | 46–89 | 47–69 | 46–89 | 69–83 | |
BCVA (logMAR) | |||||
Mean ± SD | 1.65 ± 0.79 | 0.08 ± 0.11 | 1.80 ± 0.54 | 2.36 ± 0.25 | 0.000 |
Range | 0.00–2.60 | 0.0–0.22 | 0.16–2.30 | 2.00–2.60 | |
ART (sec) | |||||
Mean ± SD | 26.70 ± 14.27 | 20.80 ± 8.67 | 29.03 ± 19.47 | 24.20 ± 6.61 | 0.504 |
Range | 13–100 | 13–34 | 14–100 | 17–35 | |
Duration of start to IAT after onset (hr) | |||||
Mean ± SD | 16.96 ± 16.93 | 20.70 ± 29.80 | 17.69 ± 15.73 | 8.20 ± 5.77 | 0.323 |
Range | 0.50–74.50 | 6.00–74.00 | 3.00–74.50 | 0.50–15.50 | |
Underlying diseases | |||||
Hypertension | 21 (47.73) | 1 | 17 | 3 | 0.704 |
Diabetes mellitus | 10 (22.73) | 0 | 7 | 3 | 0.063 |
Hyperlipidemia | 7 (15.91) | 1 | 5 | 1 | 0.951 |
Myocardial infarction | 4 (9.09) | 0 | 3 | 1 | 0.543 |
Values are presented as number (%).
CRAO = central retinal artery occlusion; SD = standard deviation; BCVA = best-corrected visual acuity; logMAR = logarithmic minimum angle of resolution; ART = arm-to-retinal time; IAT = intra-arterial thrombolysis.
Kruskal-Wallis test and the
chi-squared tests according to the results of the Kolmogorov-Smirnov test.
Exclusion criteria
Criteria |
---|
Ocular factors |
Branch retinal artery occlusion |
Combined central retinal vein occlusion |
Elevated intraocular pressure |
Existed ocular problems decreasing visual function |
General factors |
Uncontrolled hypertension (systolic blood pressure >200 mmHg) |
Previous history of heart attack, intracranial bleeding or surgery, cerebral infarction |
Recently treatment with antithrombotic drugs |
Coagulation disorder |
Allergic reaction to the contrast agent |
Visual improvement at the last follow-up after intra-arterial thrombolysis therapy according to stage of CRAO
Incomplete CRAO | Subtotal CRAO | Total CRAO | ||
---|---|---|---|---|
Total patients | 5 | 34 | 5 | 0.002 |
Significant visual improvement |
0 | 17 (50) | 0 | |
Partial visual improvement |
2 (40) | 1 (2.94) | 0 | |
No visual improvement |
3 (60) | 16 (47.06) | 5 (100) |
Values are presented as number (%).
CRAO = central retinal artery occlusion.
chi-squared test;
Significant visual improvement of ≥0.3 logMAR;
Visual improvement of <0.3 logMAR;
No visual acuity change.
Recovery of central retinal artery perfusion after intra-arterial thrombolysis therapy according to the stage of CRAO
Stage of CRAO | Reperfusion | No reperfusion |
---|---|---|
Incomplete CRAO | 5 (100) | 0 |
Subtotal CRAO | 31 (91.18) | 3 (8.82) |
Total CRAO | 4 (80) | 1 (20) |
Total patients | 40 (90.91) | 4 (9.09) |
Values are presented as number (%).
CRAO = central retinal artery occlusion.
Complication after intra-arterial thrombolysis
Complication | No. of patients |
---|---|
Dizziness | 9 (20.45) |
Headache | 8 (18.18) |
Intracranial hemorrhage | 2 (4.55) |
Itching sensation | 2 (4.55) |
Hand tremors | 2 (4.55) |
Retinal artery reocclusion | 1 (2.27) |
Ocular pain | 1 (2.27) |
Tinnitus | 1 (2.27) |
Ptosis | 1 (2.27) |
Values are presented as number (%).