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. 2025 Sep 26;15:33244. doi: 10.1038/s41598-025-18419-7

Incidence and risk factors associated with ischemic cerebrovascular disease in patients with retinal artery occlusion: a systematic review and meta-analysis

Thananop Pothikamjorn 1, Chutibhorn Charnnarong 1, Paweena Susantitaphong 2,3, Supharat Jariyakosol 4,5,✉
PMCID: PMC12475233  PMID: 41006752

Abstract

This study investigates the incidence of ischemic cerebrovascular disease (CVD), including ischemic stroke, silent stroke, and transient ischemic attack (TIA) or amaurosis fugax (AF), in patients with retinal artery occlusion (RAO). Subgroup analyses focus on RAO type and study site, exploring the association between stroke occurrence and RAO types, alongside potential stroke risk factors. Two authors independently conducted a systematic review of PubMed, Embase, and SCOPUS databases adhering to PRISMA guidelines. Our PROSPERO registration number is CRD42022354977. The analysis of 101,952 patients in 46 studies, revealed a high incidence of ischemic CVD in RAO patients:13.6% (11.5–15.9) overall, 14.4% (11.4–18.0) central retinal artery occlusion (CRAO), and 22.2% (13.5–34.3) branch retinal artery occlusion (BRAO). Patients with CRAO had a higher risk of ischemic CVD, OR 1.59 (1.45–1.75) compared to BRAO. Patients with RAO had an OR of 2.75 (2.11–3.58) for ischemic CVD compared to non-RAO patients. Risk factors significantly associated with ischemic CVD in RAO patients included smoking (OR 1.16), atrial fibrillation (OR 1.32), dyslipidemia (OR 1.30), chronic heart failure (OR 1.51), and valvular heart disease (OR 1.60). These findings highlight the need for rigorous stroke screening, close monitoring, and aggressive management of modifiable risk factors in RAO patients to reduce their stroke risk.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-025-18419-7.

Keywords: Ischemic stroke, Retinal artery occlusion, Central retinal artery occlusion, Branch retinal artery occlusion, Incidence, Meta-analysis

Subject terms: Diseases, Medical research, Neurology, Risk factors

Introduction

Cerebrovascular disease (CVD), commonly known as stroke, stands as the leading cause of global disability and the second leading cause of mortality, according to the World Stroke Organization. Over the past two decades, the incidence of stroke has surged by 70%, accompanied by a 43% increase in stroke-related fatalities1. Noteworthy risk factors for stroke include age, race, gender, family history of stroke, physical inactivity, smoking, and metabolic disorders such as hypertension, diabetes mellitus, dyslipidemia, and obesity2. Given its profound impact on individuals, families, and society, stroke remains a critical public health concern, underscoring the crucial role of prevention and early detection in mitigating its burden.

Stroke can be classified into two primary types: ischemic and hemorrhagic. Establishing a screening protocol for conditions predisposing individuals to stroke plays a vital role in reducing the global burden of disease. This study focuses primarily on retinal artery occlusion (RAO) due to its analogous pathogenesis to ischemic stroke. RAO entails the occlusion of retinal arteries leading to retinal ischemia. The etiology of occlusion may stem from thrombus, emboli, vasculitis, or vasospasm. Non-arteritic cases, caused by emboli or thrombus, share a pathogenesis similar to ischemic stroke3.

Recognizing acute retinal ischemia as akin to acute cerebral ischemia, both the American Stroke Association and American Heart Association acknowledge shared risk factors and etiologies4. Previous studies indicate that patients with RAO may develop strokes at various intervals5,6. However, surveillance for stroke in all subtypes of RAO patients remains insufficient. Therefore, individuals with RAO should undergo evaluation for stroke to facilitate early detection and appropriate treatment initiation. This study aims to estimate the incidence, the strength of association, and potential risk factors for developing ischemic stroke, diagnosed through clinical symptoms or imaging, in patients with all subtypes of RAO.

Results

Study and patient characteristics

Initially, we retrieved 2,395 studies from the three databases. After removing 1,148 duplicates and excluding 1,137 studies based on title and abstract screening, we conducted a full-text review of 110 studies. Out of these, 64 studies were excluded due to irrelevant study populations and outcomes, resulting in 46 studies being included in our systematic review and meta-analysis. Among these, 45 studies were included for the incidence of stroke, while 1 study7 with the same cohort as the one8 used for the incidence of stroke was used in risk factor analyses (Fig. 1). We excluded studies that reported 0 outcomes of interest in each specific outcome due to the accuracy of the study’s objective. The risk of bias by the Egger test demonstrated no publication bias in all groups except silent stroke post-RAO and post-central retinal artery occlusion (CRAO), ischemic CVD and ischemic stroke in patients with branch retinal artery occlusion (BRAO), and ischemic CVD in patients with CRAO versus patients with BRAO. Characteristics and risk of bias of the 46 studies were reported in Table 1. Publication bias is reported in Tables 2, 3, 4 and 5, and heterogeneity is reported in Tables 2, 3, 4, 5, 6 and 7 using the I² values. Detailed quality assessments using the Newcastle–Ottawa Scale for cohort and cross-sectional studies, and the Joanna Briggs Institute Critical Appraisal Checklist for case series, were presented in Supplement Tables 1–3.

Fig. 1.

Fig. 1

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Flow diagram for retrieving and processing article selection.

Table 1.

Characteristics and risk of bias of the 46 studies.

Study Published year Region Study design Type of RAO included Study date Age (mean, years) Follow-up duration Risk of bias
1975-Appen10 1975 North America Case series CRAO 1945–1973 54.3 17 days-492 months 4
1977-Savino39 1977 North America Case series CRAO, BRAO 1962–1973 62 NS 5
1986-Sheng43 1986 North America Case series CRAO 1970–1985 61* 34 months (carotid endarterectomy), 48 months (conservative) 5
2001-Babikian14 2001 North America Case series CRAO, BRAO September 8, 1997-June 30, 1999 68.8 1 and 3 months 5
2003-Butz15 2003 Europe Case series CRAO 7 years 64.6 NS 5
2004-Chin18 2004 Asia-Pacific Case series CRAO, BRAO June 1, 1997-August 31, 2003 57 24 months 9
2005-Arnold11 2005 Europe Cross-sectional CRAO January 1990–March 2003 63.4 (thrombolysis), 62.8 (conventional) NS 2
2010-Rudkin-Clinical characteristics37 2010 Asia-Pacific Case series CRAO 1996–2006 56.6 (JHH cohort), 75.9 (FMC cohort) 11.2 months (JHH cohort), 35.4 months (FMC cohort) 7
2010-Rudkin-Vascular risk factors38 2010 Asia-Pacific Case series CRAO 1997-September 2008 73 35 months 6
2012-Chang17 2012 Asia-Pacific cohort CRAO, BRAO, RAO January 1999–December 2006 60.14 36 months 9
2012-Helenius22 2012 North America Cross-sectional CRAO, BRAO 2000–2008 64 68 h 5
2013-Ahn9 2013 Asia-Pacific Case series CRAO January 2003 –December 2012 58.3 (IAT), 64.5 (standard treatment) 120 months 6
2013-Christiansen20 2013 Europe Cohort CRAO, BRAO 1997–2008 81 (RAO), 78 (control) 7 days 4
2014-Lee30 2014 Asia-Pacific Case series CRAO, BRAO June 2005–December 2012 58.1 (CRAO), 58.7 (BRAO) NS 7
2015-Callizo16 2015 Europe Cross-sectional CRAO September 2002–November 2007 62.2 1 month 3
2015-Lauda28 2015 Europe Cross-sectional CRAO, BRAO January 2008–July 2013 75 (stroke), 76 (silent stroke), 70 (no stroke) 1 month 5
2015-Park36 2015 Asia-Pacific Case series CRAO 2009–2010 61.62 12 months 6
2016-Rim6 2016 Asia-Pacific Cohort CRAO, RAO January 2004–December 2013 NS 48 months 7
2017-Golsari48 2017 Europe Cross sectional CRAO, BRAO 2017 69* NS 5
2017-Hong23 2017 Asia-Pacific Case series CRAO, BRAO September 2003–June 2013 60.8 12 months 5
2018-French21 2018 North America Cohort CRAO 2013 NS 6 months 4
2018-Lavin29 2018 North America Case series CRAO January 2009–December 2017 65.1 24 months 6
2018-Zhang47 2018 North America Cross-sectional CRAO, BRAO February 2013–June 2016. 64.5 36 months 3
2019-Avery12 2019 North America Cohort CRAO, BRAO October 2008–September 2013 72.5 36 months 4
2019-Chodnicki19 2019 North America Case series CRAO January 1, 2001–September 9, 2016 69.9 15 days 5
2019-Kang25 2019 Asia-Pacific Case series CRAO January 1, 1998–December 31, 2013 62.7 (aspirin), 61.9 (aspirin-naive) 12 months 7
2019-Mir34 2019 North America Cross-sectional CRAO 2003–2014 68.24 NS 4
2020-Ayrignac13 2020 Europe Case series CRAO, BRAO January 2015–December 2016 72* 3 months 7
2020-Laczynski27 2020 North America Case series CRAO, BRAO 2004–2018 66 27 months* 8
2020-Leisser32 2020 Europe Cohort CRAO, BRAO 2014–2018 71 12 months 5
2020-Schorr40 2020 North America Cohort CRAO, BRAO, RAO January 1, 2013–September 30, 2015 66.8 12 months maximum 4
2020-Shaikh42 2020 North America Case series RAO 2002–2013 NS NS 9
2021-Hoyer24 2021 Europe Case series CRAO January 2016–August 2020 72.13 NS 3
2021-Kim26 2021 Asia-Pacific Case series CRAO, BRAO September 2003–October 2018 64.7 1 month 8
2021-Lee31 2021 North America Cross-sectional NA-CRAO January 2017–August 2020 66.4 8.3 months 2
2021-Roskal-Walek7 2021 Europe Case series CRAO, BRAO 2010–2020 70 132 months 8
2021-Vestergaard46 2021 Europe Case series RAO 2000–2018 69.8 until death, outcome, or December 31, 2018 6
2022-Chodnicki5 2022 North America Cohort CRAO January 1, 2001–September 9, 2016 72* 15 days 4
2022-Liu33 2022 Asia-Pacific Case series CRAO, BRAO 2011–2021 54* 60 months 7
2022-Roskal-Walek8 2022 Europe Cohort RAO 2009–2022 70.09 144 months 6
2022-Schonecker50 2022 Europe Case series CRAO, BRAO January 2015–June 2020. 69.4 12 months 7
2022-Scoles41 2022 North America Cohort CRAO, BRAO January 1, 2004–December 31, 2016 74.6 6 months 6
2022-Suri45 2022 North America Case series RAO 2016–2018 69 6 months 8
2023-Gao49 2023 Asia-Pacific Case series CRAO, BRAO January 2014–December 2021 60.5 22.5 months (IAT), 29.5 months (conservative) 8
2023-Ørskov35 2023 Europe Case series RAO January 1, 1995–December 31, 2018 69.2 12 months 8
2023-Smith44 2023 North America Case series CRAO March 1, 2018–March 1, 2020 73.3 7 days–33 months 5
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*Median.

RAO: Retinal artery occlusion, BRAO: Branch retinal artery occlusion, CRAO: Central retinal artery occlusion, IAT: Intra-Arterial Thrombolysis, NS: Not specified.

Table 2.

Incidence of all types of ischemic cerebrovascular disease in different types of RAO.

Articles included (n) Cases (n) Pooled incidence Heterogeneity Egger’s test
(95% CI) p-value I2% p-value
Retinal artery occlusion
 Ischemic CVD post-RAO 45 10,172 13.6 (11.5–15.9) < 0.01 98.1 < 0.01 0.5
 Ischemic stroke post-RAO 42 9402 9.6 (8.2–11.2) < 0.01 97.4 < 0.01 0.6
 Silent stroke post-RAO 11 226 14.0 (8.6, 22.0) < 0.01 90.1 < 0.01 0.01
 TIA/AF post-RAO 16 544 3.6 (2.1, 6.0) < 0.01 91.3 < 0.01 0.4
Central retinal artery occlusion
 Ischemic CVD post-CRAO 31 4179 14.4 (11.4, 18.0) < 0.01 96.5 < 0.01 0.99
 Ischemic stroke post-CRAO 29 3575 9.6 (7.7, 11.9) < 0.01 94.1 < 0.01 0.3
 Silent stroke post-CRAO 10 160 12.6 (7.0, 21.8) < 0.01 90.2 < 0.01 0.02
 TIA/AF post-CRAO 11 444 2.5 (2.3, 2.7) < 0.01 0 0.79 0.98
Branch retinal artery occlusion
 Ischemic CVD post-BRAO 12 1037 22.2 (13.5, 34.3) < 0.01 93.4 < 0.01 0.01
 Ischemic stroke post-BRAO 11 988 13.9 (9.8, 19.4) < 0.01 73.9 < 0.01 0.01
 Silent stroke post-BRAO 4 41 30.5 (23.3, 38.9) < 0.01 0 0.53 0.15
 TIA/AF post-BRAO 2 8 2.4 (1.0, 5.6) < 0.01 13.05 0.28 NA
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RAO: Retinal artery occlusion, CRAO: Central retinal artery occlusion, BRAO: Branch retinal artery occlusion, CVD: Cerebrovascular diseases, TIA: Transient ischemic attack, AF: Amaurosis fugax, CI: Confidence interval, n: Number, NA: Not available.

Table 3.

Incidences of all types of ischemic cerebrovascular disease in RAO patients; subgroup analysis by study location.

Subgroup analysis Articles included (n) Cases (n) Pooled incidence Heterogeneity Egger’s test
95% CI p-value I2% p-value
Ischemic CVD post-RAO
 Asia-Pacific 13 622 13.3 (7.2, 23.2) < 0.01 97.8 < 0.01 NA
 Europe 13 1926 15.2 (10.5, 21.4) < 0.01 97.3 < 0.01 NA
 North America 19 7624 11.9 (9.5, 14.7) < 0.01 98.5 < 0.01 NA
Ischemic stroke post-RAO
 Asia-Pacific 12 501 10.2 (6.7, 15.4) < 0.01 94 < 0.01 NA
 Europe 11 1834 10.1 (6.5, 15.3) < 0.01 97.6 < 0.01 NA
 North America 19 7067 8.5 (6.9, 10.4) < 0.01 97.8 < 0.01 NA
Silent stroke post-RAO
 Asia-Pacific 4 108 18.6 (9.7,32.6) < 0.01 84.1 < 0.01 NA
 Europe 4 83 17.3 (10.4, 27.4) < 0.01 76.4 0.005 NA
 North America 3 35 6.2 (0.6,43.4) 0.03 96.5 < 0.01 NA
TIA/AF post-RAO
 Asia-Pacific 2 13 3.1 (1.2, 7.7) < 0.01 54.6 0.14 NA
 Europe 6 9 3.4 (1.8, 6.4) < 0.01 0 0.82 NA
 North America 8 522 3.8 (1.8, 8.0) < 0.01 95.8 < 0.01 NA
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RAO: Retinal artery occlusion, CRAO: Central retinal artery occlusion, BRAO: Branch retinal artery occlusion, CVD: Cerebrovascular diseases, TIA: Transient ischemic attack, AF: Amaurosis fugax, CI: Confidence interval, n: Number, NA: Not available.

Table 4.

Risk of ischemic cerebrovascular disease in patients with CRAO compared with BRAO, and RAO compared with non-RAO.

Articles included (n) Cases (n) Pooled Incidence Heterogeneity Egger’s test
95% CI p-value I2% p-value
Ischemic stroke post-CRAO vs. BRAO 8 1905 1.48 (0.92, 2.39) 0.11 37.4 0.13 0.21
Silent stroke post-CRAO vs. BRAO 3 32 0.81 (0.31, 2.16) 0.68 0 0.64 0.1
Ischemic CVD post-CRAO vs. BRAO 9 1922 1.59 (1.45–1.75) < 0.01 0 0.48 0.04
Ischemic stroke post-RAO vs. non-RAO 4 480 2.47 (1.99, 3.07) < 0.01 0 0.78 0.46
Ischemic CVD post-RAO vs. non-RAO 5 15,443 2.75 (2.11, 3.58) < 0.01 43.3 0.13 0.93
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RAO: Retinal artery occlusion, CRAO: Central retinal artery occlusion, BRAO: Branch retinal artery occlusion, CVD: Cerebrovascular diseases, CI: Confidence interval, n: Number.

Table 5.

Factors associated with ischemic cerebrovascular disease in patients with RAO.

Risk factors Articles included (n) Cases (n) Pooled incidence Heterogeneity Egger’s test
OR (95% CI) p-value I2% p-value
Age > 45 3 13 1.27 (0.36, 4.54) 0.71 0 0.6 0.3
Female 6 558 1.03 (0.92–1.16) 0.59 0 0.49 0.14
Hypertension 5 890 1.32 (0.85, 2.05) 0.22 29.8 0.22 0.93
Diabetes mellitus 5 282 1.09 (0.95, 1.25) 0.22 0 0.55 0.07
Previous Stroke or TIA 3 17 1.40 (0.66, 2.94) 0.38 0 0.7 0.21
Current smoking 4 387 1.16 (1.02, 1.31) 0.02 0 0.65 0.5
Atrial fibrillation 2 185 1.32 (1.12, 1.55) 0.001 0 0.81 NA
Dyslipidemia 2 602 1.30 (1.16, 1.47) < 0.01 0 0.57 NA
Chronic heart failure 2 117 1.51 (1.24, 1.84) < 0.01 0 0.82 NA
Myocardial ischemia 2 0 0.71 (0.07, 6.88) 0.77 0 0.74 NA
Valvular heart disease 2 156 1.60 (1.34, 1.91) < 0.01 0 0.34 NA
Systemic lupus erythematosus 2 1 1.27 (0.12, 13.30) 0.84 0 0.99 NA
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RAO: Retinal artery occlusion, TIA: Transient ischemic attack, CI: Confidence interval, OR: Odds ratio, n: Number, NA: Not available.

Table 6.

Incidences of ischemic cerebrovascular disease in different types of RAO; subgroup analysis by follow-up period.

Subgroup analysis by follow-up period Articles included (n) Cases (n) Pooled incidence Heterogeneity
OR (95% CI) I2% p-value
Ischemic CVD post-RAO
 Less than 6 months 7 340 8.8 (3.9–18.8) 90.8 < 0.01
 6–12 months 7 5815 8.0 (4.7–13.3) 98.0 < 0.01
 More than 12 months 10 259 11.2 (6.7–18.2) 58.5 0.01
Ischemic CVD post-CRAO
 Less than 6 months 7 181 17.7 (7.6–35.9) 95.7 < 0.01
 6–12 months 8 1350 8.2 (4.9–13.4) 97.7 < 0.01
 More than 12 months 10 77 15.6 (8.7–26.3) 79.9 < 0.01
Ischemic CVD post-BRAO
 Less than 6 months 4 67 16.7 (10.1–26.5) 44.4 0.15
 6−12 months 2 909 10.4 (4.8–20.9) 54.2 0.14
 More than 12 months 4 56 14.9 (8.7–24.3) 34.4 0.21
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CI: Confidence interval, BRAO: Branch retinal artery occlusion, CRAO: Central retinal artery occlusion, CVD: Cerebrovascular diseases, n: Number, RAO: Retinal artery occlusion.

Table 7.

Risk of ischemic cerebrovascular disease in patients with CRAO compared with BRAO, and RAO compared with non-RAO; subgroup analysis by follow-up period.

Subgroup analysis by follow-up period Articles included (n) Cases (n) Pooled incidence Heterogeneity
OR (95% CI) p-value I2% p-value
Ischemic CVD post-CRAO vs. BRAO
 Less than 6 months 1 9 1.20 (0.32, 4.47) 0.77 0 1
 6−12 months 2 902 1.60 (1.45, 1.77) < 0.01 0 0.37
 More than 12 months 5 40 1.01 (0.44, 2.31) 0.99 37.4 0.17
Ischemic CVD post-RAO vs. non-RAO
 Less than 6 months 1 75 3.94 (2.86, 5.44) < 0.01 0 1
 More than 12 months 3 158 2.37 (1.94, 2.91) < 0.01 0 0.89
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CI: Confidence interval, BRAO: Branch retinal artery occlusion, CRAO: Central retinal artery occlusion, CVD: Cerebrovascular diseases, n: Number, OR: Odds ratio, RAO: Retinal artery occlusion.

There were 101,952 patients with RAO who underwent neurological screening and were included in the study. Of these, 37,307 patients were diagnosed with CRAO, 12,595 were BRAO patients, and 2,187 were patients with other RAO, including ophthalmic artery occlusion, ocular ischemic syndrome, and vascular transient monocular vision loss.

Incidence of all types of ischemic cerebrovascular disease in different types of RAO

Forty-two studies5,6,8–47 reported the incidence of ischemic stroke in patients with RAO. Eleven studies5,9,16,19,24,26,28–30,33,48 reported the incidence of silent stroke in patients with RAO. Sixteen studies5,11,14–17,19,24,27,32,34,39,40,44,49,50 reported the incidence of transient ischemic attack (TIA) or amaurosis fugax (AF) in patients with RAO. Overall, forty-five studies5,6,8–50 found that the incidence of ischemic CVD in patients with RAO was 13.6% (95% CI: 11.5–15.9).

Twenty-nine studies5,9–13,15–19,21,22,24–26,28–32,34,36–38,41,43,44,47 reported the incidence of ischemic stroke in patients with CRAO. Ten studies5,9,16,19,24,26,28–30,48 reported the incidence of silent stroke in patients with CRAO. Eleven studies5,11,15–17,19,24,32,34,44,50 reported the incidence of TIA or AF in patients with CRAO. A total of thirty-one studies5,9–13,15–19,21,22,24–26,28–32,34,36–38,41,43,44,47,48,50 reported the incidence of ischemic CVD in patients with CRAO was 14.4% (95% CI: 11.4–18.0).

Eleven studies12,13,17,18,22,26,28,30,32,41,47 reported the incidence of ischemic stroke in patients with BRAO. Four studies26,28,30,48 reported the incidence of silent stroke in patients with BRAO. Two studies17,32 reported the incidence of TIA or AF in patients with BRAO. A total of twelve studies12,13,17,18,22,26,28,30,32,41,47,48 reported the incidence of ischemic CVD in patients with BRAO was 22.2% (95% CI: 13.5, 34.3). The incidences of all types of ischemic CVD in different types of RAO were reported in Table 2.

Subgroup analysis by study site revealed a comparable incidence of ischemic CVD in RAO patients, which is 13.3% (95% CI: 7.2, 23.2) in Asia-Pacific, 15.2% (95% CI: 10.5, 21.4) in Europe, and 11.9% (95% CI: 9.5, 14.7) in North America (Table 3).

Risk of ischemic cerebrovascular disease in patients with and without RAO

Four studies6,8,11,17 reported the OR of incidence of ischemic stroke in patients with RAO compared with patients without RAO. A total of five studies6,8,11,17,20 reported the OR of incidence of ischemic CVD in patients with RAO compared with patients without RAO. Having RAO was found to have an association with an increased risk of ischemic CVD occurrence, the OR was 2.75 (95% CI: 2.11, 3.58) (Fig. 2). We could not calculate the OR of incidence of silent stroke or TIA or AF due to insufficient data.

Fig. 2.

Fig. 2

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Forest plot of odd ratios of ischemic cerebrovascular disease occurrence in patients with and without RAO.

Risk of ischemic cerebrovascular disease in patients with CRAO compared with BRAO

Eight studies8,12,17,18,30,32,41,47 reported the OR of the incidence of ischemic stroke in patients with CRAO compared with patients with BRAO. Three studies13,30,48 reported the OR of the incidence of silent stroke in patients with CRAO compared with patients with BRAO. We reported OR of 1.59 (95% CI: 1.45–1.75) of incidence of ischemic CVD in patients with CRAO compared with BRAO patients (Fig. 3). The OR of the incidence of each type of ischemic CVD in patients with CRAO compared with patients with BRAO is shown in Table 4.

Fig. 3.

Fig. 3

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Forest plot of odd ratios of ischemic cerebrovascular disease occurrence in patients with CRAO compared with patients with BRAO.

Factors associated with ischemic cerebrovascular disease in patients with RAO

We found a significant association in an increased risk of ischemic CVD with an OR of 1.30 (95% CI: 1.16, 1.47), 1.51 (95% CI: 1.24, 1.84), and 1.60 (95% CI: 1.34, 1.91), in patients with RAO with dyslipidemia, chronic heart failure, and valvular heart disease, respectively (Table 5).

Three studies10,15,18 reported the OR of incidence of ischemic CVD associated with patient’s age. Six studies10,13,15,18,22,42 reported the OR of incidence of ischemic CVD associated with gender in patients with RAO. Five studies10,13,18,22,42 reported the OR of incidence of ischemic CVD in patients with hypertension and RAO. Five studies10,13,18,22,42 reported the OR of incidence of ischemic CVD in patients with diabetes mellitus and with RAO. Four studies13,18,22,42 reported the OR of incidence of ischemic CVD associated with smoking status patients with RAO. Three studies10,13,22 reported the OR of incidence of ischemic CVD and in patients with prior stroke or TIA and with RAO. Two studies reported13,42 the OR of incidence of ischemic CVD in patients with atrial fibrillation, dyslipidemia, and with RAO. Two studies10,42 reported the OR of incidence of ischemic CVD in patients with chronic heart failure and valvular disease, and with RAO. Two studies10,18 reported the OR of incidence of ischemic CVD in patients with myocardial infarction and systemic lupus erythematosus, and with RAO.

Subgroup analysis by follow-up period

Thirty-eight5,6,8–10,12–14,16–23,25–29,31–33,35–38,40–47,49,50 studies reported the exact follow-up period for the subgroup analysis of the incidence of ischemic CVD in patients with RAO. Twenty-five studies5,9,12,13,16–19,21,22,25,26,28,29,31,32,36–38,41,43,47,50 reported the exact follow-up period for the subgroup analysis of the incidence of ischemic CVD in patients with CRAO. Ten studies12,13,17,18,22,26,28,32,41,47 provided the exact follow-up period for the subgroup analysis of the incidence of ischemic CVD in patients with BRAO. The incidences of ischemic CVD across different types of RAO, stratified by follow-up period, were detailed in Table 6.

Eight studies7,12,17,18,30,32,41,47 reported the exact follow-up period for the subgroup analysis of the odds ratio (OR) for ischemic CVD in patients with CRAO compared to patients with BRAO. Four studies6,8,17,20 reported the exact follow-up period for the subgroup analysis of the OR for ischemic CVD in patients with RAO compared to patients without RAO. The risks of ischemic CVD in patients with CRAO versus BRAO, and RAO versus non-RAO, stratified by follow-up period, were detailed in Table 7.

Discussion

To the best of our knowledge, this is the first systematic review and meta-analysis to estimate the incidence and risk factors of ischemic CVD, including ischemic stroke, silent stroke, and TIA or AF in patients with each RAO subtype. Our study reports a high incidence, 13.6% of ischemic CVD in patients with any RAO. The incidence has high heterogeneity, with an I2% of 98.1%, which could be attributed to the different inclusion criteria of each study, stroke diagnostic criteria, patient baseline characteristics, and the different management after the diagnosis of RAO. We report 2 times the odds of having a stroke in patients with RAO compared with patients without RAO, OR of 2.75, which aligns with previous studies that mentioned the OR to be 2.03–2.466,8,17,20.

Previous systematic reviews and meta-analyses reported that patient with CRAO or BRAO has a higher risk of having a stroke6,8,17,20,51. The incidence of ischemic stroke was 30% in patients with CRAO and 25% in patients with BRAO51. However, for silent stroke, the incidences were lower at 22% for CRAO and 29% for BRAO51.

Notably, our findings revealed a higher incidence of silent stroke, with an incidence of 14%, 12.6%, and 30.5% in patients with RAO, CRAO, and BRAO, respectively, compared to patients with ischemic stroke in patients with RAO 9.6%, CRAO 9.6%, and BRAO 13.9%. We hypothesized that silent stroke may be more prevalent than commonly assumed, particularly in patients with BRAO, underscoring the importance of vigilance and diagnostic efforts for silent stroke in these individuals despite the absence of clinical symptoms. Since diagnosing ischemic and silent stroke are crucial for patients’ outcomes considering the need for treatment, extending to the prevention of both types of strokes. Clear guidelines for stroke screening and surveillance post-RAO will result in an improvement in RAO management, decreasing stroke morbidity and mortality over time.

Our study also addressed the gap in comparing patients with CRAO and BRAO within the same cohort. We found that patients with CRAO had higher odds of 1.59 (95% CI: 1.45–1.75) of having ischemic CVD. This may be because CRAO involves larger vessels, indicating a more severe systemic disease, which could lead to an ischemic stroke. Conversely, the higher odds of silent stroke in BRAO patients, 0.81 (95% CI: 0.31, 2.16), could be due to the more subtle nature of smaller vessel occlusions. While CRAO presents with more evident retinal ischemia and immediate visual impairment due to its involvement of the central retinal artery, BRAO may often go unnoticed initially due to its peripheral nature and potentially milder symptoms. However, the underlying mechanisms of vascular compromise in both conditions involve systemic factors such as atherosclerosis and hypertension, which are closely linked to an increased risk of stroke.

Subgroup analysis by follow-up duration revealed that ischemic CVD risk persists over time across all RAO subtypes. Patients with RAO demonstrated a markedly elevated risk of ischemic CVD compared to non-RAO controls, particularly within the first 6 months of follow-up, underscoring the critical need for early risk screening and stroke prevention. Differentiating stroke risk by RAO subtype provides valuable insights for clinical decision-making. CRAO and BRAO may require distinct follow-up protocols and surveillance intensity, as we found a higher pooled incidence of silent stroke post-BRAO. Guideline development should reflect these subtype-specific considerations to optimize patient outcomes.

Encompassing studies from diverse regions, we also examined the incidence of stroke in subgroups based on the study site. Subgroup analyses of stroke in patients with RAO revealed comparable incidences of ischemic CVD across regions: 13.3% in Asia-Pacific, 15.2% in Europe, and 11.9% in North America. However, the incidence of silent stroke was significantly higher in Europe (17.3%) and Asia-Pacific (18.6%) compared to North America (6.2%). These differences may reflect variations in healthcare systems, including access to diagnostic tools and regular health check-ups, as well as cultural attitudes and socioeconomic factors influencing detection rates. Regional disparities in stroke incidence highlight the importance of context-specific clinical pathways. Tailored screening strategies may improve the detection of silent strokes in underdiagnosed populations. International guidelines should consider these differences to ensure equitable care.

For baseline characteristics of patients with every type of RAO in developing ischemic CVD, we found numerous significant factors. Nevertheless, current data may suggest a possibility of these characteristics becoming risk factors, considering their relevance to the pathophysiology of stroke and development. There is an urgent need to identify risk factors in patients with RAO, allowing for risk modification strategies and multidisciplinary care can be tailored to reduce the mortality and morbidity of RAO. Early identification of high-risk RAO patients, particularly those with current smoking, atrial fibrillation, dyslipidemia, chronic heart failure, and valvular heart diseases, is critical for effective stroke prevention. Personalized risk stratification could inform more targeted interventions to reduce the development of ischemic CVD. This underscores the value of collaborative, multidisciplinary management approaches.

A further gap in our research was the attempt to extract the period between the initial symptoms of RAO and the onset of ischemic stroke. Although various studies have been designed to collect time-to-diagnosis data, the results vary. Some studies reported concurrent stroke, while others collected data within 7 days30,47, 15 days5,19, or up to 30 days16,25,36. This variability suggests that implementing standardized surveillance and follow-up duration in clinical practice for patients with different types of RAO could be beneficial. We encourage future studies on patients with RAO to collect and report the time-to-event to gather more insights into the field. Our review process excluded non-English manuscripts, which introduces selection bias, potentially overlooking important research from non-English-speaking regions. However, this approach ensures consistency and minimizes the risk of misinterpretation, given our detailed study definitions. Future inclusion of translated studies is warranted to address this limitation. Furthermore, the pooled data is inhomogeneous due to variations in study designs as some excluded patients with a history of stroke, which is a major risk factor for recurrent stroke. To conclude the potential risk factors of stroke in patients with RAO, a larger worldwide cohort study should be conducted to announce risk factor modification guidelines to decrease the incidence of stroke in patients with RAO.

The high incidence of ischemic cardiovascular disease in RAO patients emphasizes the need for thorough stroke screening, vigilant monitoring, and early intervention. The strong association between RAO and strokes necessitates comprehensive neurovascular evaluations and aggressive management of modifiable risk factors. Establishing a stroke surveillance system, especially for patients with BRAO, is crucial to reduce stroke risk. Collaborative management involving stroke specialists and ophthalmologists is recommended to enhance patient outcomes.

Methods

Search strategy

Two authors (TP and CC) performed this systematic search independently in 3 databases including PubMed, Embase, and SCOPUS from inception to 13 January 2023. Our search terms included combinations of RAO-related terms and stroke-related terms ((“CRAO” OR “Central Retinal Artery Occlusion” OR “BRAO” OR “Branch Retinal Artery Occlusion” OR “Retinal Artery Occlusion” OR “CLRAO” OR “cilioretinal artery occlusion” OR “Ophthalmic artery occlusion” OR “Acute retinal arterial occlusive disorder” OR “Acute retinal arterial ischemic disorder” OR “Retinal ischemia”) AND (“Acute Ischemic stroke” OR “Acute stroke” OR “Ischemic stroke” OR “Brain infarction” OR “Cerebral infarct” OR “Cerebral infarction” OR “Cerebrovascular disease” OR “Cerebrovascular diseases” OR “Cerebrovascular accident” OR “Silent stroke” OR “Silent brain infarction”)). The complete search terms for each database were available in the Supplements. We report this study with guidance from the Joanna Briggs Institute Manual for Evidence Synthesis and Guidelines for Accurate and Transparent Health Estimates Reporting statement52–54, per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We conducted a manual hand search from reference lists and citation tracking for eligible studies. The International Prospective Register of Systematic Reviews (PROSPERO) registration number is CRD42022354977.

Eligibility criteria

RAO was defined as having a clinical presentation of sudden visual loss and classic ophthalmoscopic finding, with or without additional imaging modalities, such as fundus fluorescence angiography, and optical coherence tomography. The types of RAO include CRAO, BRAO, and cilioretinal artery occlusion (CLRAO), depending on the affected vessel.

Stroke was defined as an episode of acute neurological dysfunction presumed to be caused by ischemia or hemorrhage, persisting ≥ 24 h or until death. The addition of brain imaging, such as computed tomography or magnetic resonance imaging, proves to help diagnose stroke. Ischemic stroke was defined as an episode of neurological dysfunction caused by focal cerebral or spinal infarction. Silent stroke was characterized as a presence of imaging or neuropathological evidence of central nervous system infarction, without a history of acute neurological dysfunction attributable to the lesion. TIA was defined as a brief episode of neurological dysfunction caused by focal brain or retinal ischemia, with clinical symptoms lasting less than 24 h, typically lasting less than one hour, and without evidence of acute infarction. AF was defined as transient loss of vision, involving partial or entire visual field, in one or both eyes lasting between 2 and 30 min55. Ischemic CVD includes ischemic stroke combined with silent stroke and TIA or AF.

Our primary outcome was to determine the incidence of ischemic stroke in patients with RAO, with a subgroup analysis of each type including CRAO, BRAO, and CLRAO. Additionally, our secondary aim was to determine the incidence of silent stroke and TIA or AF within the same patient population. We also aimed to explore the relationship between ischemic CVD incidence and RAO subtype (CRAO vs. BRAO), as well as identify potential risk factors such as age, sex, smoking status, history of previous stroke, and underlying diseases including hypertension, diabetes mellitus, atrial fibrillation, dyslipidemia, chronic heart failure, myocardial infarction, valvular heart disease, and systemic lupus erythematosus in the development of ischemic CVD in patients with RAO.

Study selection

The screening process was conducted in the Covidence systematic review software (Veritas Health Innovation). Two authors (TP and CC) independently reviewed the included studies and selected all observational studies in which the incidence of stroke or silent stroke was provided or could be calculated. Conference abstracts and case reports were excluded due to the accuracy and unavailability of data required for incidence calculation. If more than 1 publication was based on the same cohort or population and reported the same outcomes, only the latest publication with the largest population was included. Studies involving arteritic RAO (e.g., vasculitis), autoimmune causes (e.g., Susac syndrome), missing data, or reporting zero events for outcomes of interest will be excluded. The conflict of the selected studies will be discussed between the two authors and solved by mutual agreement. We used the web-based Google Translate to translate non-English-language abstracts during abstract screening. For the full-text review, non-English language studies were excluded due to difficulties in translation and full comprehension.

Data extraction and quality assessment

Two authors (TP and CC) independently extracted numbers of patients with ischemic stroke, silent stroke, and TIA or AF to calculate the incidence of stroke. The combined outcomes of ischemic stroke, silent stroke, and TIA were referred to as ischemic CVD. Participant age, follow-up duration, study date, region, and publication year were additional variables that were sought. Differences in data extraction between the two authors will be discussed and solved by the other author (SJ). After the analyses, data were available only for CRAO and BRAO. Next, two authors (TP and CC) individually appraised the quality of studies, resolving disagreements through discussion and consensus.

The Newcastle–Ottawa Scale (NOS) was employed to assess the quality of the included cohort and cross-sectional studies56, while the Joanna Briggs Institute (JBI) Critical Appraisal Checklist was applied to evaluate case series57.

Data synthesis and analysis

Odds ratios (OR) were derived from available studies. All combined estimates were accompanied by 95% confidence intervals (95% CI). We utilized the I2 statistics of less than 50% indicating low heterogeneity and above 50% denoting substantial heterogeneity, although we accompanied the use of the random effects model to every analysis due to heterogeneity nature of the incidence study.

Subgroup analyses were conducted to explore global trends in ischemic stroke incidence based on the presence of RAO, types of RAO (CRAO and BRAO), and study sites (Asia Pacific, Europe, or North America). Publication bias was formally assessed using Egger’s test. The meta-analysis analysis was conducted using the Comprehensive Meta-Analysis Software version 2.0 (www.meta-analysis.com).

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1 (33KB, docx)

Acknowledgements

We would like to extend our gratitude to the librarians at the Faculty of Medicine, Chulalongkorn University for their contribution of retrieving full papers of studies that were not available on the databases.

Author contributions

TP: study design, literature search, data extraction, quality assessment of the studies, data analysis, statistical analysis, manuscript writing, and critical review. CC: study design, literature search, data extraction, quality assessment of the studies, data analysis, manuscript writing, and critical review. SJ: supervision, study design, data extraction, data analysis, manuscript writing, and critical review. PS: statistical analysis, manuscript writing, and critical review.

Data availability

The data for our systematic review and meta-analysis are publicly available. Study protocol and dataset can be requested at supharat.j@chula.ac.th.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1 (33KB, docx)

Data Availability Statement

The data for our systematic review and meta-analysis are publicly available. Study protocol and dataset can be requested at supharat.j@chula.ac.th.

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