Acute Central Retinal Artery Occlusion Seen Within 24 hours at a Tertiary Institution

Abstract

Objectives:

Acute central retinal artery occlusion (CRAO) is an emergency with poor visual outcome. Intravenous thrombolysis within 4.5 hours of vision loss is safe and may improve vision, but is rarely administered because of frequent delays in presentation. We describe a subgroup of CRAO patients presenting within 24 hours of vision loss to a tertiary care center affiliated with a comprehensive stroke center.

Materials and Methods:

Retrospective review of 181 consecutive CRAO patients seen at our institution from 2010–2020.

Results:

Out of 181 CRAO patients, 62 (34%) presented within 24 hours of vision loss and tended to live closer to the hospital. These patients were more likely to be admitted to the hospital and receive comprehensive stroke work-up compared to patients who presented after 24 hours of vision loss. Patients presenting after 24 hours did not necessarily receive prior appropriate work-up at outside institutions. Conservative treatments for CRAO were administered to 20/181 patients, and only 3 patients received intravenous thrombolysis.

Conclusions:

Patients with CRAO do not present to the emergency department fast enough and diagnosis of CRAO is often delayed. Despite having a protocol in place, only 3/181 patients received IV thrombolysis, emphasizing the difficulty in administering very acute treatments for CRAO. Public education regarding CRAO is necessary to improve presentation times, management, and visual outcomes. Hospitals need to develop accelerated diagnostic pathway protocols for patients with acute vision loss so that CRAO patients may be diagnosed and be considered for potential acute treatments as quickly as possible.

INTRODUCTION

Acute non-arteritic central retinal artery occlusion (CRAO) is an emergency with poor visual outcome, occurring with an incidence of approximately 1–2 per 100,000 annually (1,2). Non-arteritic CRAO is analogous to an ischemic cerebral stroke (3–5), as both processes share the same etiological and risk factor profile and have the same systemic implications. Numerous recent studies have emphasized that acute non-arteritic CRAO and cerebral stroke should be managed similarly (2–5). However, a 2018 national US survey of university-affiliated teaching hospitals found that only 20% of respondents had a formal multidisciplinary guideline/protocol in place for CRAO (6). Thirty-five percent of respondents did not routinely send their CRAO patients to the emergency department (ED) for evaluation and treatment (6).

There are currently no evidence-based (e.g., supported by a randomized clinical trial) and uniformly accepted treatment options for non-arteritic CRAO. Less than 20% of patients regain functional visual acuity without intervention (2,7). Traditionally, once temporal arteritis is ruled-out, patients with CRAO have been treated with so-called “conservative treatments”, including ocular massage, anterior chamber paracentesis, intraocular pressure-lowering eyedrops, laser thrombectomy, and hemodilution, with variable anecdotal success (6,8). As in acute ischemic cerebral stroke, early arterial recanalization with thrombolysis appears to be the most promising of treatment options for CRAO thus far (6,9–11). Whether intravenous thrombolysis within 4.5 hours of vision loss or intra-arterial thrombolysis, likely within 6 hours of vision loss, should be used remains debated (3,11,12). There are currently two ongoing randomized clinical trials evaluating intravenous thrombolysis in acute CRAO within 4.5 hours of vision loss in Europe (Clinicaltrials.gov TenCRAOS NCT04526951, and THEIA NCT03197194). Unfortunately, recruitment remains slow, consistent with the difficulty in making the diagnosis of CRAO within such a short time window. Better understanding of why most CRAO patients do not present rapidly to emergency facilities affiliated with a stroke center would help future educational interventions. The aim of our study was to evaluate the characteristics and management of CRAO patients that presented within 24 hours of vision loss to our tertiary institution affiliated with a comprehensive stroke center and outpatient ophthalmology clinic, over the past decade.

METHODS

This study was approved by the Emory Institutional Review Board. Informed consent was waived because data were deidentified. This was a retrospective observational cohort study of all adult patients diagnosed with acute CRAO from 2010 – 2020 at one tertiary academic institution, including an ED affiliated with a comprehensive stroke center and an affiliated outpatient ophthalmology clinic. We searched our electronic medical records for all patients diagnosed with CRAO. We only included patients with a definite diagnosis of CRAO seen at our institution for acute vision loss or CRAO between January 1, 2010 and July 31, 2020. Patients with an unclear diagnosis, incidental prior history of CRAO, pediatric patients, and those evaluated at a satellite clinic were not included. Time to presentation to our institution (ED affiliated with a comprehensive stroke center or our outpatient eye clinic) was recorded and patients were divided into 3 groups: those presenting to our institution within 4.5 hours of vision loss (group 1), those presenting between 4.5 and 24 hours (group 2), and those presenting after 24 hours (group 3). Baseline patient demographic data such as age, sex, race, body mass index (BMI) and distance travelled to our institution were collected. Time to presentation after vision loss onset, number of healthcare providers seen prior to presenting to our institution, results of stroke workup and treatment were also noted.

Statistical analysis:

Data are expressed either as mean ± standard deviation or median with interquartile range for continuous data, as indicated, and as percentages for categorical data. Statistical analysis was performed using R: A language and environment for statistical computing (R Foundation for Statistical Computing, http://www.R-project.org) by BBB. Fisher’s exact test and chi-square tests were used to compare proportions between groups with α set to 0.05.

RESULTS

Of 181 patients included in this study, 80 (44.2%) were women and 101 (55.8%) were men, with a mean age of 67.0 ± 13.3 years and mean BMI of 29.2 ± 6.82 kg/m². Races represented were 87 (48.1%) White, 78 (43.1%) Black, 6 (3.3%) Asian, 2 (1.1%) Hispanic, and 8 (4.4%) were unspecified. Patients travelled a median of 25.1 miles (IQR, 13.6 – 56.8; range, 0 – 930.0) from their home zip code to our institution within a median presentation time of 72 hours (IQR 10.5 – 336, range 0 – 13,140). Seven patients were already admitted to our institution at the time of their CRAO for other reasons and were considered to have travelled zero miles with zero hours to presentation. These were sick inpatients (two patients died during their admission) and none received any acute treatments for CRAO. Due to their medical complexity, these 7 inpatients were excluded from further analysis.

Excluding those 7 inpatients, 21 patients presented to our institution within 4.5 hours (group 1), 41 patients presented between 4.5 and 24 hours (group 2), and 112 patients presented after 24 hours (group 3). There were no demographic differences (age, sex, race, BMI) among the three groups (Table 1). Patients who presented faster (groups 1 and 2) lived closer to the hospital compared to patients in group 3 (p <0.001).

Table 1.

Patient demographics and distance traveled for 181 CRAO patients based on time to presentation to our institution

	≤ 4.5 hours n = 21	4.6 – 24 hours n = 41	> 24 hours n = 112	P
Median Age (years)	65 IQR:50 – 75 Range: 20 – 81	70 IQR: 62 – 78 Range: 28 – 88	70 IQR: 60 – 77 Range: 35 – 101	0.283
Sex
Male, n (%)	15 (71)	22 (54)	61 (54)	0.329
Female, n (%)	6 (29)	19 (46)	51 (46)
Race
Black, n (%)	11 (52)	17 (41)	51 (46)
White, n (%)	7 (33)	20 (49)	53 (47)	0.449
Asian, n (%)	2 (9.5)	2 (4.9)	2 (1.8)
Hispanic, n (%)	1 (4.8)	0	1 (0.89)
Unspecified, n (%)	0	2 (4.9)	5 (4.5)
Median body mass index (kg/m2)	28.7 IQR: 27.3 – 30.2 Range: 21.8 – 47.9	27.2 IQR: 25.1 – 32.7 Range: 20 – 67.5	27.7 IQR: 24.1 – 32.2 Range: 17.6 – 48.8	0.761
Median distance traveled (miles)	12.6 IQR: 5.7 – 20.5 Range: 2.7 – 41	24.7 IQR: 15.4 – 58.5 Range: 5.0 – 72.8	33.7 IQR: 19.2 – 69.8 Range: 2.4 – 930	<0.001

IQR: interquartile range

More patients in groups 1 and 2 were admitted to the hospital (p <0.001) and received appropriate stroke work-up, including neuroimaging such as CT head and MRI brain, vascular imaging, and cardiac evaluation (Table 2). One patient in group 2, and two patients in group 3 had temporal artery biopsy-proven giant cell arteritis and received intravenous high-dose steroids. None of these patients presented within 4.5 hours of visual loss.

Table 2.

Admissions and investigations of CRAO patients based on time of presentation to our institution

	≤ 4.5 hours n = 21	4.6 – 24 hours n = 41	> 24 hours n = 112	P
Admission, n (%)	19/21 (90%)	28/41 (68%)	43/104 (41%)	< 0.001
CT Head, n (%)	15/20 (75%)	23/30 (77%)	43/95 (45%)	0.001
MRI Brain, n (%)	17/21 (81%)	29/38 (76%)	52/105 (50%)	0.002
Vascular imaging, n (%)	19/20 (95%)	34/37 (92%)	73/102 (72%)	0.006
Cardiac evaluation, n (%)	17/21 (81%)	31/37 (84%)	57/101 (56%)	0.003

None of the patients in group 3 received a full stroke work-up prior to arriving to our institution (Table 3). Indeed, of the patients presenting to our institution after 24 hours, only 35/110 (32%) had a CT head, 27/110 (25%) had a brain MRI, 42/110 (38%) had vascular imaging, and 32/110 (29%) had cardiac evaluation at an outside facility prior to arrival to our institution.

Table 3.

Investigations performed at outside facilities prior to arrival to our institution

	≤ 4.5 hours n = 21	4.6 – 24 hours n = 41	> 24 hours n = 112	P
CT Head, n (%)	0	8/39 (21%)	35/110 (32%)	0.007
MRI brain, n (%)	0	4/39 (10%)	27/110 (25%)	0.006
Vascular imaging, n (%)	0	5/39 (13%)	42/110 (38%)	< 0.001
Cardiac evaluation, n (%)	0	3/39 (8%)	32/110 (29%)	< 0.001

A greater proportion of group 1 patients received attempted acute interventions for their CRAO compared to patients in groups 2 and 3 (Table 4). Intravenous thrombolysis was administered in only 3/21 (14%) of patients in group 1 (p = 0.002), and no patients in groups 2 or 3 received this treatment. Of the 62 patients seen within 24 hours of vision loss, 22.5% received so-called conservative treatments (Table 4). Only 2 patients received hyperbaric oxygen therapy, both 2–3 days after onset of CRAO. Of the 21 patients who were diagnosed with CRAO within 4.5 hours of vision loss (group 1), 17 did not receive intravenous thrombolysis. Nine of these patients had a delayed diagnosis (7 patients) or misdiagnosis (2 patients) in the ED. Three patients had contraindications to intravenous thrombolysis, and one patient declined therapy when it was offered. In 4 patients, the onset of vision loss could not be determined precisely as it was apparent upon waking from sleep, and these patients were excluded from receiving thrombolysis by the neurology team. For one patient evaluated within 4.5 hours, there was no discussion of thrombolysis as a treatment option in the medical record.

Table 4.

Acute treatments performed for CRAO patients based on time of presentation to our institution

	≤ 4.5 hours n = 21	4.6 – 24 hours n = 41	> 24 hours n = 112	P
Ocular massage, n (%)	7/ 21 (33%)	4/41 (10%)	2/112 (2%)	< 0.001
Anterior chamber paracentesis, n (%)	2/21 (10%)	1/41 (2%)	2/112 (2%)	0.142
Hyperbaric oxygen, n (%)	0	0	2/112 (2%)	1.00
Intravenous thrombolysis, n (%)	3/21 (14%)	0	0	0.002

DISCUSSION

Our institution evaluated 181 CRAO patients from 2010 – 2020, of which only 62 patients (34%) presented within 24 hours of vision loss. These patients did not differ demographically from patients arriving to our institution after 24 hours, except that patients who presented early lived closer to our institution. Importantly, we found that more patients who presented to our institution within 24 hours received appropriate stroke work-up compared to those who were seen after 24 hours. Although it is well-established that CRAO is the retinal equivalent of an ischemic cerebral stroke (3,4), there is significant variability in the management and treatment of acute CRAO. A 2018 US survey of university-affiliated teaching hospitals showed that only 20% of respondents had a formal guideline or protocol in place for CRAO, and 35% of academic hospitals did not routinely send their CRAO patients to the ED for evaluation and treatment (6).

Appropriate stroke work-up for non-arteritic CRAO patients is critical. Indeed, previous studies have shown that at least 24 – 37% of CRAO patients have asymptomatic silent cerebral infarctions on diffusion-weighted brain MRI at the time of CRAO (13,14), corresponding to a high risk of a cerebral stroke and underlying cardiovascular disease, especially in the 24–72-hour period after onset of vision loss (3,15,16). In the southern US, where our institution is located, the combined risk of stroke, myocardial infarction, and death within a 2-year period of follow-up can be up to 32% after a CRAO (14). A comprehensive stroke work-up, including brain MRI, vascular imaging, and cardiac evaluation, is a crucial part of secondary stroke prevention in patients with CRAO, regardless of their time to presentation after vision loss. The antiquated practice of only obtaining a carotid ultrasound with an outpatient follow-up with primary care for optimization of vascular risk factors for patients with CRAO should be updated (16–19); as shown in our study, and recently by others (20), outpatient evaluation is often delayed and difficult to arrange in a timely manner. Patients with acute CRAO should immediately be sent for evaluation and stroke work-up at an ED affiliated with a stroke center.

Despite having a CRAO protocol in place at our institution, only 3 of 181 patients presenting to our institution with CRAO over the last decade received intravenous thrombolysis. None received intra-arterial thrombolysis. Unfortunately, 9 potentially eligible patients did not receive thrombolysis due to delay in CRAO diagnosis in our own ED, highlighting how difficult it can be to make the diagnosis, especially in the acute phase when retinal edema and the classic funduscopic appearance (cherry red spot) may not be obvious. In these instances of uncertainty, urgent optical coherence tomography (OCT) of the macula allows for rapid diagnosis by demonstrating inner retinal edema (21,22). At institutions that do not have access to an ophthalmology service, diagnostic tools such as non-mydriatic fundus photography (23) and OCT can facilitate timely CRAO diagnosis by an off-site ophthalmologist utilizing teleophthalmology or existing telestroke networks (17).

This study demonstrates that our current challenge lies in the fact that patients with acute vision loss are often not evaluated quickly enough by eye care providers and patients with diagnosed acute CRAO are not usually referred to an ED associated with a stroke center in time for acute intervention. This is in keeping with recent similar studies (18,19). Even when the patients arrive early and are eligible for thrombolysis or other very acute treatments, they rarely receive it because early diagnosis of CRAO may be difficult outside the eye clinic. This makes it very challenging to prospectively study treatment options for CRAO in clinical trials. The two ongoing concurrent prospective clinical trials in Europe utilize similar protocols for intravenous thrombolysis within 4.5 hours of vision loss onset with the goal to increase the number of included patients and maximize statistical power. Our study highlights the need to better educate the public to call emergency services and present immediately to an ED affiliated with a stroke center instead of to their local primary care provider or even local eyecare provider when they experience acute vision loss. National campaigns such as the American Heart Association’s FAST acronym for stroke have largely been successful in ensuring timely presentation for acute cerebral strokes; adding B for balance and E for eyes to form ‘BE FAST’ ensures that we also better capture patients with posterior circulation strokes and CRAO (24). Education of healthcare providers regarding the urgency of CRAO diagnosis and the impact it may have on their patients’ future risks of stroke, myocardial infarction, and death is also essential. Resources should be directed towards alerting community practitioners in ophthalmology, optometry, neurology, primary care, and emergency medicine that acute, painless monocular visual loss can be a stroke analogue that needs to be assessed in an ED affiliated with a stroke center, rather than with outpatient investigations.

The retrospective nature of our study has its limitations and is subject to issues such as incomplete data, especially for those patients who were assessed at outside hospitals or outpatient clinics. It also assumes complete and accurate documentation on the part of the physicians who saw the patients who were included in the analysis. However, looking back at how CRAO was managed at our institution over the past decade has also yielded valuable information allowing for recognition of areas for potential improvement in expedited triage of patients with acute vision loss and CRAO. Our results also only reflect a single tertiary institution in a large urban area and may not be generalizable to other parts of the United States or other countries.

CONCLUSION

Educational campaigns have historically been successful for improving the management of acute cerebral stroke and myocardial infarction. There is reason to believe that education regarding acute vision loss and CRAO could result in similar success, with improved management and visual and neurologic outcomes for these patients. Hospitals and healthcare networks need to develop simple interdisciplinary accelerated diagnostic pathways and protocols for patients with acute vision loss so that CRAO patients can be diagnosed and considered for potential acute treatments and clinical trials as quickly as possible. Existing tele-stroke networks could be used to facilitate remote diagnosis of CRAO in hospitals without ophthalmology coverage using non-mydriatic fundus photography and OCT, possibly with the integration of artificial intelligence into user-friendly portable fundus cameras (25,26). The only way we will be able to help CRAO patients improve vision loss, prevent secondary cerebral stroke, and improve their quality of life is to have a paradigm shift in the way healthcare teams think about acute painless vision loss. When it comes to CRAO, “time is retina” much like “time is brain” for ischemic stroke (12).