Neovascular glaucoma (NVG), caused by ocular ischemia, is a serious ocular disease complicated by intractably increased intraocular pressure. Cerebrovascular accidents are classified into ischemic and hemorrhagic stroke. Based on the similar pathogenic mechanisms of NVG and ischemic stroke, we investigated the relationship between NVG and stroke by using a nationally representative sample. This study included 416 NVG patients and 4160 controls. Medical comorbidities were also evaluated. The cumulative incidence of ischemic stroke was 15.6% higher in the NVG cohort than in the control cohort (
Neovascular glaucoma (NVG), caused by ocular ischemia, is a serious ocular disease complicated by intractably increased intraocular pressure (IIOP). Ocular ischemia results from retinal vein occlusion, diabetic retinopathy (DMRP), or inflammatory ocular diseases. Additionally, the vascular endothelial growth factor (VEGF) level may increase in the anterior segment of the eye, leading to the neovascularization of the iris, angle, and trabecular meshwork [
Cerebrovascular accidents, which are a global burden among aging populations [
Few studies have investigated the relationship between NVG and stroke. However, the similar pathogenic mechanisms of NVG and ischemic stroke warrant an exploration of the potential relationship between the two diseases. In this retrospective study, we examined this relationship by using a nationally representative sample obtained from the Longitudinal Health Insurance Research Database of Taiwan.
This retrospective cohort study analyzed secondary data obtained from the Longitudinal Health Insurance Research Database 2000 (LHID2000). LHID2000 contains the health claims data of 1,000,000 beneficiaries randomly sampled from the Registry of Beneficiaries of the National Health Insurance (NHI) program of Taiwan. The universal NHI program was established in March 1995 and provides health-care coverage to more than 99% of the 23.74 million residents of Taiwan [
Figure
Schematic of selection process of participants in the NGV and control cohorts.
The endpoint of this study was the development of stroke (ICD-9-CM codes 430–438), which was subclassified into ischemic stroke (ICD-9-CM codes 433–438) and hemorrhagic stroke (ICD-9-CM codes 430–432) events. All patients were followed up from their index date to the endpoint, withdrawal from the NHI program, or until December 31, 2011. Baseline medical comorbidities included diabetes mellitus (DM) (ICD-9-CM code 250), hypertension (ICD-9-CM codes 401–405), hyperlipidemia (ICD-9-CM code 272), and coronary artery disease (ICD-9-CM codes 410–414). Baseline ocular comorbidities included central and branch retinal vein occlusion (ICD-9-CM codes 362.35 and 362.36), DMRP (ICD-9-CM code 362.0), retinal detachment with retinal defect (ICD-9-CM code 361.00), central and branch retinal artery occlusion (ICD-9-CM codes 362.31, 362.32, and 362.33), hypertensive retinopathy (ICD-9-CM code 362.11), and uveitis (ICD-9-CM codes 053.22, 054.44, 091.52, 364.0, 364.1, 364.2, 364.3, 360.0, 360.1, 091.5, 363.21, 360.04, 091.51, 094.83, 115.02, 115.12, 115.92, 130.2, 362.18, 363.0, 363.1, and 363.2).
The chi-square test (or Fisher’s exact test) and
Comparison of demographics and comorbidities between patients with NVG and controls.
NVG ( |
Control ( |
| |||
---|---|---|---|---|---|
|
(%) |
|
(%) | ||
Age, year | 0.99 | ||||
≤49 | 87 | (20.9) | 870 | (20.9) | |
50–64 | 149 | (35.8) | 1490 | (35.8) | |
≥65 | 180 | (43.3) | 1800 | (43.3) | |
Mean (SD)# | 61.5 | (14.2) | 60.9 | (14.6) | 0.36 |
Sex | 0.99 | ||||
Female | 175 | (42.1) | 1750 | (42.1) | |
Male | 241 | (57.9) | 2410 | (57.9) | |
Medical comorbidity | |||||
Diabetes mellitus | 224 | (53.9) | 531 | (12.8) | <0.001 |
Hypertension | 300 | (72.1) | 1681 | (40.4) | <0.001 |
Hyperlipidemia | 197 | (47.4) | 995 | (23.9) | <0.001 |
Coronary artery disease | 150 | (36.1) | 795 | (19.1) | <0.001 |
Ocular comorbidity | |||||
CRVO & BRVO | 56 | (13.5) | 5 | (0.12) | <0.001 |
DMRP | 208 | (50.0) | 75 | (1.80) | <0.001 |
Retinal detachment with retinal defect§ | 18 | (4.33) | 3 | (0.07) | <0.001 |
CRAO & BRAO | 5 | (1.20) | 0 | 0.00 | — |
HTR§ | 7 | (1.68) | 1 | (0.02) | <0.001 |
Uveitis | 66 | (15.9) | 25 | (0.60) | <0.001 |
Chi-square test; #
This study included 416 patients with NVG and 4160 controls who were recruited between 2000 and 2011. Of the 416 patients with NVG, 43.3% were older than 65 years and 57.9% were men (Table
Comparison of the cumulative incidence of ischemic stroke between the NVG and control cohorts using the Kaplan-Meier method.
The incidence density rates of stroke were 3.80 and 1.19 per 10,000 person-years in the NVG and control cohorts, respectively (Table
Comparison of the incidence density rates of stroke between patients with NVG and controls stratified by demographic characteristics and comorbidities.
NVG | Crude HR (95% CI) | Adjusted HR† (95% CI) | ||||||
---|---|---|---|---|---|---|---|---|
Yes | No | |||||||
Event | PY | Rate# | Event | PY | Rate# | |||
All | 66 | 1736 | 3.80 | 257 | 21,658 | 1.19 | 3.21 (2.45–4.21) |
2.07 (1.41–3.02) |
Hemorrhagic stroke | 8 | 0.46 | 30 | 0.14 | 3.24 (1.48–7.08) |
1.15 (0.35–3.85) | ||
Ischemic stroke | 58 | 3.34 | 227 | 1.05 | 3.20 (2.40–4.28) |
2.24 (1.51–3.32) |
||
Age | ||||||||
≤49 | 7 | 470 | 1.49 | 9 | 5561 | 0.16 | 9.91 (3.68–26.7) |
1.51 (0.22–10.5) |
50–64 | 25 | 583 | 4.28 | 57 | 7833 | 0.73 | 5.71 (3.56–9.17) |
3.42 (1.97–5.95) |
≥65 | 34 | 682 | 4.98 | 191 | 8264 | 2.31 | 2.18 (1.51–3.14) |
1.83 (1.22–2.74) |
Sex | ||||||||
Female | 35 | 735 | 4.76 | 103 | 9763 | 1.06 | 4.49 (3.05–6.60) |
2.74 (1.63–4.61) |
Male | 31 | 1000 | 3.10 | 154 | 11,895 | 1.29 | 2.40 (1.63–3.53) |
1.66 (0.95–2.89) |
Medical comorbidity& | ||||||||
No | 3 | 367 | 0.82 | 55 | 11,476 | 0.48 | 1.67 (0.52–5.35) | 1.20 (0.27–5.44) |
Yes | 63 | 1368 | 4.60 | 202 | 10,182 | 1.98 | 2.34 (1.76–3.11) |
2.14 (1.43–3.19) |
Ocular comorbidity§ | ||||||||
No | 16 | 606 | 2.64 | 245 | 21,270 | 1.15 | 2.29 (1.38–3.80) |
1.82 (1.10–3.03) |
Yes | 50 | 1130 | 4.42 | 12 | 388 | 3.09 | 1.43 (0.76–2.69) | 1.93 (1.00–3.75) |
#Incidence rate per 10,000 person-years; crude HR represents relative hazard ratio. †Variables that were found to be significant in the univariable analysis and which were included in the multivariable analysis. &Medical comorbidity (having at least one comorbidity classified as a medical comorbidity (e.g., diabetes mellitus, hypertension, hyperlipidemia, or coronary artery disease)). §Ocular comorbidity (having at least one comorbidity classified as an ocular comorbidity (e.g., central and branch retinal vein occlusion, diabetic retinopathy, retinal detachment with retinal defect, central and branch retinal artery occlusion, hypertensive retinopathy, and uveitis)).
The results of univariable and multivariable Cox regression models for analyzing the risk factors for ischemic stroke are shown in Table
Hazard ratios of ischemic stroke stratified by age and comorbidities in the univariable and multivariable Cox regression models.
Variable | Crude | Adjusted† | ||
---|---|---|---|---|
HR | (95% CI) | HR | (95% CI) | |
NVG | 3.20 | (2.40–4.28) |
2.24 | (1.51–3.33) |
Age, years | 1.07 | (1.06–1.08) |
1.06 | (1.05–1.07) |
Sex (female versus male) | 1.08 | (0.85–1.36) | — | — |
Medical comorbidity | ||||
Diabetes mellitus (yes versus no) | 2.41 | (1.86–3.12) |
1.09 | (0.78–1.53) |
Hypertension (yes versus no) | 4.27 | (3.29–5.56) |
2.09 | (1.55–2.82) |
Hyperlipidemia (yes versus no) | 1.75 | (1.37–2.24) |
0.92 | (0.70–1.22) |
Coronary artery disease (yes versus no) | 2.75 | (2.16–3.50) |
1.17 | (0.90–1.52) |
Ocular comorbidity | ||||
CRVO & BRVO (yes versus no) | 2.42 | (1.08–5.45) |
0.64 | (0.27–1.51) |
DMRP (yes versus no) | 3.58 | (2.58–4.98) |
1.69 | (1.05–2.72) |
Retinal detachment with retinal defect (yes versus no) | 1.04 | (0.15–7.41) | — | — |
CRAO & BRAO (yes versus no) | — | — | — | — |
HTR (yes versus no) | 2.78 | (0.39–19.8) | — | — |
Uveitis (yes versus no) | 2.20 | (1.17–4.14) |
1.02 | (0.53–1.99) |
Crude HR represents the relative hazard ratio. †Variables that were found to be significant in the univariable analysis and which were included in the multivariable analysis.
Several studies have revealed that patients with glaucoma have higher risks of some systemic diseases. For example, primary open-angle glaucoma has been significantly associated with cerebral microinfarcts [
This finding is particularly important from a pathogenic perspective. The major etiology of NVG includes DMRP, central retinal vein occlusion, and ocular ischemic syndrome [
The effect that sex has on the risk of stroke should also be addressed. In our study population, the aHR of stroke for the NVG cohort versus the control cohort was 2.74 (95% CI = 1.63–4.61) for women and 1.66 (95% CI = 0.95–2.89) for men. According to our review of the literature, stroke event rates are lower in women than in men, but sex comparisons based on age-adjusted rates mask key differences [
In contradiction to the presumed belief that aging is positively associated with the risk of stroke [
Additionally, our results showed that patients in the NVG cohort with any one medical comorbidity had a significantly higher risk of stroke (aHR = 2.14, 95% CI = 1.43–3.19) than those with no comorbidities. However, further analysis indicated that among all medical comorbidities, the risk of ischemic stroke was significantly higher only in patients with hypertension (aHR = 2.09, 95% CI = 1.55–2.82). Evidence has shown that metabolic syndrome and its main definitional components, including high blood pressure and hyperglycemia, are strongly associated with an increased risk of stroke [
Our results also indicated that the risk of stroke was statistically significant in patients with NVG who did not have ocular comorbidities (aHR = 1.82, 95% CI = 1.10–3.03) and was significant in patients with NVG who had ocular comorbidities (aHR = 1.93, 95% CI = 1.00–3.75). However, further analysis indicated that the risk of ischemic stroke was only borderline significantly higher (
Despite these promising results, our study has some limitations. First, LHID2000 does not contain detailed information on potential confounding factors, such as diet, smoking, obesity, lifestyle factors, or family history of glaucoma or stroke [
In conclusion, patients with NVG have a higher risk of ischemic stroke, but not hemorrhagic stroke. Ophthalmologists should be aware of this risk when managing cases of NVG.
The authors do not have any possible conflicts of interest.
All authors are responsible for the content and writing of this paper.
This study is supported in part by the Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW106-TDU-B-212-113004); China Medical University Hospital; Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10601010036); Taiwan Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005); Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; and Katsuzo and Kiyo Aoshima Memorial Funds, Japan.