Introduction: The aim of the study was to investigate the clinical efficacy of superselective ophthalmic artery thrombolysis for central retinal artery occlusion (CRAO). Methods: Retrospective study of CRAO patients who attended the Department of Ophthalmology of Affiliated Hospital of Weifang Medical University from January 2022 to July 2023, 138 CRAO patients with onset time of 1–3 days were selected for the study. Among them, 86 patients refused thrombolytic treatment and chose to adopt traditional treatment, which was categorized as the control group; 52 patients adopted superselective ophthalmic artery thrombolytic treatment, which was categorized as the observation group. The visual acuity of the patients treated with traditional modality on the 4th day after the onset of the disease and the visual acuity of the patients treated with superselective ophthalmic artery thrombolysis on the 1st postoperative day were recorded, and the visual acuity improvement after different modalities of treatment was compared between the two groups. Results: In the control group, 77 (89.5%) of the treated patients had no improvement in visual acuity, 9 (10.5%) had improvement, 0 (0.0%) had significant improvement, and the total improvement was 9 (10.5%); in the observation group, 18 (34.6%) of the treated patients had no improvement in visual acuity, 21 (40.4%) had improvement, 13 (25.0%) had significant improvement, and the total improvement was 34 (65.4%). The total improvement rate of treatment in the observation group was 65.4%, which was significantly higher than the 10.5% in the control group, and the difference was statistically significant (p < 0.05). Conclusion: Superselective ophthalmic artery thrombolysis for patients with CRAO is clinically effective, promotes improvement in patient vision, and has a high safety profile.

Acute central retinal artery occlusion (CRAO) is a rare disease that often leads to acute painless loss of vision in one eye and has a poor prognosis. In acute CRAO cases, which are about 0.85 per 100,000 people [1], most are between 65 and 70 years of age and usually have risk factors for atherosclerotic disease. The etiology of CRAO is still not well understood, and the potential causative mechanisms are broadly categorized as [2]: embolic obstruction and vascular occlusion. For the treatment of CRAO, there is not yet a recognized treatment method, and the current mainstream treatment modalities [3] are observational therapy; increasing ocular perfusion by vasodilating blood vessels (e.g., sublingual isosorbide nitrate); clearing the obstruction by physical methods (e.g., ocular massage); increasing the ocular perfusion by lowering the intraocular pressure (IOP) (e.g., anterior chamber puncture, intravenous acetazolamide, etc.); oxygenation therapy; and arterial and venous thrombolysis and so on. In order to investigate the optimal treatment for patients with CRAO, we retrospectively analyzed the clinical data of 52 patients who underwent superselective ophthalmic arterial thrombolysis in our hospital and 86 patients who underwent traditional modality of treatment in our hospital during the same period of time, and compared and analyzed their clinical outcomes before and after treatment.

Research Target

Clinical data of CRAO patients who attended the ophthalmology department of the Affiliated Hospital of Weifang Medical University from January 2022 to July 2023 were retrospectively analyzed. Patients with CRAO diagnosed by an experienced ophthalmologist (diagnosis based on fundus photography showing cherry erythema of the fundus, ophthalmic coherence tomography (OCT) showing a thickened retina, and fluorescein fundus angiography (FFA) showing an embolus or a significant slowing of the blood flow rate), and exclusion of branch retinal artery occlusion (BRAO), and arteritis CRAO. We ultimately identified 138 patients with acute thromboembolic CRAO, all of whom started treatment within 1–3 days after onset. Among them, 52 patients underwent superselective ophthalmic artery thrombolysis intervention treatment under the following conditions: patients with CRAO diagnosed by an ophthalmologist; patients with intracranial hemorrhage ruled out by a CT scan of the skull; patients with an expected time from the onset of symptoms to interventional thrombolysis of 1–3 days; patients with no clinical or laboratory test contraindications to thrombolysis; and patients with a signed informed consent with an understanding of the potential risks and benefits of the procedure (risks: bleeding at the puncture site, toxicity and allergic reactions to contrast media, bleeding and necrosis of organs, dislodging of the embolus, intracranial hematoma, fundus and intracranial hemorrhage, exacerbation of pre-existing underlying diseases). Among them, 86 patients underwent traditional treatment in the following situations: the patient had been treated with conventional modalities in other hospitals before coming to the ophthalmology department of our hospital; the patient had serious clinical or laboratory test contraindications to thrombolysis (abnormal coagulation function, platelet count <100 × 109/L, suffering from hematologic diseases such as hemophilia, history of severe craniocerebral trauma or stroke in the last 3 months, Intracranial or intravertebral surgery in the last 3 months, cranial CT or MRI suggesting large infarcts); and the patient refused to undergo superselective ophthalmic artery thrombolysis intervention and agreed to be treated with conventional modalities instead, after being informed of the potential risks and benefits of the procedure. This study protocol was reviewed and the need for approval was waived by the Affiliated Hospital of Weifang Medical University. All treatment modalities were performed in accordance with relevant guidelines and regulations.

Research Method

In the control group, we carried out at least two traditional treatment methods, including eye massage, IOP reduction (anterior chamber puncture), blood vessel expansion (taking isosorbide nitrate), and oxygen inhalation, according to the wishes of the patients, the actual situation of the patients, and the wishes of the doctors. The observation group adopted surgical treatment and gave patients superselective ophthalmic artery interventional thrombolytic therapy. Surgical method: under local anesthesia, the surgeon punctured the patient’s femoral artery with the Seldinger technique, connected the 6F catheter sheath, and performed the aortic arch and, bilateral internal carotid arteries, external carotid arteries, and bilateral vertebral arteries angiography to get a comprehensive understanding of the patient’s intracranial circulation. The surgeon in the left position under the working angle, in the case of X-ray fluoroscopy, with a guidewire to guide the 6Fguiding catheter placed in the patient’s common carotid artery opening; the surgeon in the road map shows the ophthalmic artery situation, with Syncro-14 micro-guidewire to guide the echelon-10 micro-catheter into the patient’s ophthalmic artery initiation, the imaging to confirm that there is no error, will be 500,000 units of urokinase (manufacturer: Shandong Beida Gaoke Huatai Pharmaceutical Co., Ltd; Approval No. National Drug License H37020116) was slowly injected into the patient’s ophthalmic artery, and the changes in the patient’s visual acuity during the operation were observed and recorded.

Outcome Measures

(1) Record the visual acuity of patients in the observation group before receiving treatment and the visual acuity on the first day after treatment; record the visual acuity of patients in the control group before receiving treatment and the visual acuity on the fourth day after the onset of treatment. Compare and analyze the no-improvement rate, improvement rate, obvious improvement rate and total improvement rate (total improvement rate = improvement rate+obvious improvement rate) of the patients treated in the observation group and that of the patients treated in the control group; compare and analyze the changes in visual acuity of the patients in the observation group before and after the treatment and that of the patients in the control group before and after the treatment. (2) The occurrence of complications during and after treatment was recorded for patients in the observer and control groups.

Efficacy Evaluation Criteria

We categorized the patients’ visual acuity evaluation criteria into five levels [4]: level 1 no light perception; level 2 light perception; level 3 visual manual; level 4 visual counting finger; and level 5 can see the symbols of the labeled visual acuity chart. Patients with grade 5 visual acuity were examined using the international standard visual acuity chart for best corrected visual acuity, which was recorded as log MAR visual acuity. Based on the patient’s post-treatment review of visual acuity, we categorized the improvement in visual acuity as no improvement, improvement, or significant improvement. Patients with no improvement in the level of visual acuity after treatment compared to the level of visual acuity before treatment or patients with no improvement in the number of rows of the visual acuity chart after treatment compared to the number of rows of the visual acuity chart before treatment were categorized as having no improvement. Patients were classified as improved if their post-treatment visual acuity level increased by 1 level from the pre-treatment visual acuity level or if the number of rows on the patient’s post-treatment visual acuity chart increased by 1–2 rows from the number of rows on the patient’s pre-treatment visual acuity chart. Patients were classified as having significant improvement if their post-treatment visual acuity level increased by 2 or more levels from the pre-treatment visual acuity level, or if the number of rows in the patient’s visual acuity meter increased by 3 or more rows from the pre-treatment visual acuity meter rows.

Statistical Methods

All data were statistically analyzed using SPSS 25.0. Measurement data were expressed as X¯±S and t-test was used for comparison between groups; count data were expressed as rate (%), and χ2 test was used for comparison between groups. p < 0.05 was regarded as statistically significant difference.

General Information

After screening by the above criteria, a total of 138 patients were included in this study. There were 86 patients in the control group and 52 patients in the observation group. Age, gender (male, woman), underlying disease (hypertension, diabetes, hyperlipidemia), affected eye (right, left), and time from patient onset to treatment were comparatively analyzed for the patients in the control and observation groups (Table 1). The difference between the baseline indicators of the patients in the control and observation groups was not statistically significant (p > 0.05) (Table 1).

Table 1.

Comparison of general information between control and observation groups

CategoryControl group (n = 86)Observation group (n = 52)χ2/tp value
Age 58.81±6.40 56.38±12.33 1.317 0.473 
Gender, n (%)   0.004 1.000 
 Male 60 (69.8) 36 (69.2)   
 Woman 26 (30.2) 16 (30.8)   
Underlying disease, n (%)     
 Hypertension 38 (44.2) 26 (50.0) 0.440 0.507 
 Diabetes 17 (19.8) 11 (21.2) 0.039 0.844 
 Hyperlipidemia 10 (11.6) 6 (11.5) 0.000 0.987 
Affected eye, n (%)   0.029 0.865 
 Right 36 (41.9) 21 (40.4)   
 Left 50 (58.1) 31 (59.6)   
Time from patient onset to treatment 48.33±13.18 48.00±14.56 0.135 0.192 
CategoryControl group (n = 86)Observation group (n = 52)χ2/tp value
Age 58.81±6.40 56.38±12.33 1.317 0.473 
Gender, n (%)   0.004 1.000 
 Male 60 (69.8) 36 (69.2)   
 Woman 26 (30.2) 16 (30.8)   
Underlying disease, n (%)     
 Hypertension 38 (44.2) 26 (50.0) 0.440 0.507 
 Diabetes 17 (19.8) 11 (21.2) 0.039 0.844 
 Hyperlipidemia 10 (11.6) 6 (11.5) 0.000 0.987 
Affected eye, n (%)   0.029 0.865 
 Right 36 (41.9) 21 (40.4)   
 Left 50 (58.1) 31 (59.6)   
Time from patient onset to treatment 48.33±13.18 48.00±14.56 0.135 0.192 

Comparison of Clinical Efficacy between Patients in the Control Group and the Observation Group after Receiving Treatment

The visual acuity recovery after treatment of the patients in the control and observation groups: no improvement (rate), improvement (rate), significant improvement (rate), and total improvement (rate), were compared and analyzed (Table 2). The total treatment improvement rate of patients in the observation group was significantly higher than that of patients in the control group (p < 0.05, Table 2).

Table 2.

Comparison of clinical efficacy between patients in the control group and the observation group after receiving treatment

GroupNo improvementImprovementSignificant improvementTotal improvement
Control group (N = 86), n (%) 77 (89.5) 9 (10.5) 0 (0.0) 9 (10.5) 
Observation group (N = 52), n (%) 18 (34.6) 21 (40.4) 13 (25.0) 34 (65.4) 
χ2 49.042 49.042 49.042 45.566 
p value <0.05 <0.05 <0.05 <0.05 
GroupNo improvementImprovementSignificant improvementTotal improvement
Control group (N = 86), n (%) 77 (89.5) 9 (10.5) 0 (0.0) 9 (10.5) 
Observation group (N = 52), n (%) 18 (34.6) 21 (40.4) 13 (25.0) 34 (65.4) 
χ2 49.042 49.042 49.042 45.566 
p value <0.05 <0.05 <0.05 <0.05 

Comparison of Visual Acuity of Patients in the Control and Observation Groups before and after Treatment

The difference in best corrected visual acuity (log MAR) between control and observation group patients was not statistically significant before CRAO patients received treatment (p > 0.05, Table 3). The visual acuity of patients in the observation group on day 1 after receiving interventional thrombolytic therapy was significantly improved compared with that of patients in the control group on day 4 after the onset of the disease after receiving treatment in the traditional way, and the difference was statistically significant (p < 0.05, Table 3).

Table 3.

Comparison of visual acuity of patients in the control group and the observation group before and after receiving the treatment

CategoryControl group (n = 86)Observation group (n = 52)tp value
BCVA before treatment 2.52±1.11 2.38±1.03 0.789 0.432 
BCVA after treatment 2.46±1.15 1.68±1.18 3.815 0.000 
CategoryControl group (n = 86)Observation group (n = 52)tp value
BCVA before treatment 2.52±1.11 2.38±1.03 0.789 0.432 
BCVA after treatment 2.46±1.15 1.68±1.18 3.815 0.000 

BCVA, best corrected visual acuity.

Complications

After 52 patients with CRAO underwent superselective ophthalmic artery thrombolysis, none of them developed clinical manifestations of postoperative complications related to acute cerebral infarction, acute cerebral hemorrhage, and transient cerebral ischemia. There was also no obvious abnormality in the neurological examination performed by the physician on the patients as of the time of their discharge from the hospital.

CRAO is an ocular vascular obstructive disease that causes retinal ischemia. The onset of the disease is sudden and often leads to a sharp decrease in the patient’s vision in one eye, or even blindness, making it an ophthalmic emergency. The current etiology of CARO can be broadly categorized as [2]: embolic obstruction and vascular occlusion. Embolic obstruction may result from dislodgment of emboli (cholesterol, calcification, thrombus, mucoma, bacteria) originating in the carotid arteries or the heart; vascular occlusion may result from localized atherosclerotic plaques, giant-cell arteritis, or other types of vasculitis. Because the prognosis for patients with CRAO is extremely poor, this has forced clinicians to urgently find an optimal or accepted form of treatment, but unfortunately, no treatment is currently convincing enough. The mainstay treatment modalities include vasodilatation, physical removal of obstruction (ocular massage), reduction of IOP, improvement of erythrocyte flow dynamics (reduction of erythrocyte stiffness, hemodilution, etc.), and arteriovenous thrombolysis, to name a few [5]. Therefore, this study compared the clinical outcomes of patients with CRAO after superselective ophthalmic artery thrombolysis with those treated by traditional modalities (hospitalization for observation, IOP lowering, vasodilatation, ophthalmic massage, oxygenation, etc.).

The thrombolytic time window for CRAO patients is based on a rhesus monkey experiment [6] that shows CRAO persists for 97 min and then recanalizes with no retinal damage. However, the longer the CRAO exists after this time, the more extensive the irreversible retinal damage will be. If it lasts longer than 240 min, it will cause irreversible retinal damage on a large scale. However, the consultation time of patients is often unsatisfactory, and some patients have the expectation that the vision of the affected eye will recover on its own, which leads to the delay of the consultation time, as well as the lack of knowledge of some ophthalmologists about this disease, which misses the optimal time of treatment during the cumbersome examination [7]. However, it has been reported in the relevant literature [8] that when the onset time of CRAO patients exceeds the 4.5 h time window, the application of urokinase thrombolysis to treat non-arteritic CRAO is still effective, and the time window of thrombolysis has little effect on the therapeutic effect. A study by Ahn et al. [9] showed that patients with incomplete CRAO had a significantly higher rate of clinical visual improvement than patients with complete CRAO. The degree of central retinal artery obstruction may be more important than the time window of treatment in influencing the outcome [10]. This is why we chose superselective ophthalmic arterial thrombolysis even after the onset of the CRAO patient’s disease had exceeded 240 min, and the clinical effectiveness rate was as high as 65.4%, which was much higher than that of 10.5% for the same period of time when the treatment was carried out in the traditional way.

Taking into account the possible etiology of CRAO, we analyzed the reasons for the ineffectiveness of superselective ophthalmic arterial thrombolysis in some patients: CRAO is not always caused by embolic occlusion, but in some cases it is the result of vascular occlusion (which may be caused by localized atherosclerotic plaques, giant-cell atherosclerosis, or other types of vasculitis), and in the latter case thrombolytic therapy is ineffective. Not all CRAO caused by emboli are soluble emboli. Arruga et al. [11] found that there are usually three types of emboli leading to CRAO: 74% cholesterol emboli, 15.5% platelet fibrin thrombi and 10.5% calcified emboli, and that urokinase is only effective against platelet fibrin emboli. However, Aldrich et al. [12] concluded that the site of thrombus occlusion in patients with CRAO is at the level of the sieve plate, which is not observable on funduscopy, and therefore, the study by Arruga et al. does not necessarily truly reflect the distribution of thrombus types in patients with CRAO. In this paper, the total effective rate of CRAO patients treated with superselective ophthalmic artery thrombolysis was as high as 65.4%, which reinforces the fact that the distribution of thrombus types may be different from that of the study by Arruga et al. The distribution of thrombus types in patients with CRAO needs to be further studied and verified.

The incidence of serious complications of surgery (acute cerebral hemorrhage, acute cerebral infarction, etc.) in patients with CRAO undergoing superselective ophthalmic artery thrombolysis has been the subject of controversy and one of the reasons for the lack of acceptance of this treatment modality. Several European countries conducted studies related to intra-arterial thrombolysis (Multicenter Study of the European Assessment Group for Lysis in the Eye, EAGLE) [1] in the early 21st century, because of the failure to achieve the expected results of the procedure and the emergence of serious complications (the EAGLE study reported 44 patients, of whom 2 [4.55%] developed complications related to local intra-arterial thrombolysis [cerebral hemorrhage and cerebellar hemorrhage]), so the study had to be terminated at an early stage. However, as interventional techniques continue to mature and improve and surgical equipment continues to be upgraded, more and more clinicians are questioning these results. In the study by Ahn et al. [13], the adverse events of superselective ophthalmic artery thrombolysis were only mild cerebral infarction symptoms in 1 patient (1.8%). In the study by Tao Lei et al. [14], after 577 patients with non-arteritis CRAO were treated with arterial thrombolysis with urokinase, a total of 4 cases of procedure-related complications occurred, which accounted for only 0.7% of the total number of patients, including 1 case of acute cerebral infarction (0.2%), 2 cases of acute cerebral hemorrhage (0.3%), and 1 case of transient cerebral ischemia (0.2%). In this study, the incidence of surgery-related adverse events was even lower at 0.00%, with the possibility of a small sample size error, which needs to be further confirmed by a large sample size, multicenter study.

The clinical therapeutic effect of superselective ophthalmic artery thrombolysis for the treatment of CRAO is significantly higher than that of the traditional modality treatment. Popularizing patients’ knowledge of painless sudden monocular vision loss, as well as strengthening the linkage between ophthalmology and neurology, surgery, and interventional medicine, will enable CRAO patients to receive timely and effective treatment. Even if the onset time is more than 240 min, intra-arterial thrombolysis can still be considered, which can still improve the patient’s vision to some extent. However, this study is a single-center retrospective study with a small sample size, which has certain limitations and needs to be validated by prospective randomized controlled studies with multicenter and large sample size.

This study protocol was reviewed and the need for approval was waived by the Affiliated Hospital of Weifang Medical University. Written informed consent to participate in the study has been obtained from the participants.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

N.Y.K. wrote the manuscript. F.W. was the patient’s surgeon and revised the manuscript. Y.X. and Q.L.G. collected the patient’s clinical cases and data. M.L. analyzed and processed the data.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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