The risk of ischemic stroke significantly increases in individuals with blepharitis: A population-based study involving 424,161 patients

**Background:** Blepharitis is a common inflammatory eyelid condition affecting 37–50% of the population, particularly women over 50. Ischemic stroke (IS) accounts for >80% of cerebrovascular accidents. While inflammation and infection are recognized risk factors for stroke, the link between blepharitis and IS had not been previously investigated. This study aimed to evaluate the risk of IS in patients with blepharitis using a large nationwide population-based cohort.

**Methods:** This retrospective cohort study used data from Taiwan's National Health Insurance Research Database (NHIRD), covering >99% of the population. Patients aged ≥20 years with a new diagnosis of blepharitis (ICD-9-CM 373.0; ICD-10-CM H01.0x) between 2008 and 2018 were identified. Exclusion criteria included age <20, prior stroke/transient ischemic attack, graft-versus-host disease, HIV, Sjögren's syndrome, rheumatoid arthritis, keratoconjunctivitis, use of systemic or topical medications affecting dry eye within 4 weeks before index date, ocular surgery within 6 months, and missing data. After exclusions, 424,161 blepharitis patients were 1:1 propensity-score matched to non-blepharitis controls on sex, age, and comorbidities (hypertension, diabetes, dyslipidemia, Parkinson's disease, coronary artery disease, congestive heart failure, acute myocardial infarction, non-valvular atrial fibrillation, chronic kidney disease, chronic liver disease, peripheral vascular disease, venous thromboembolism, malignancy, smoking, obesity). The index date for cases was the first blepharitis diagnosis; for controls, a random date between 2008–2018. Follow-up continued until IS onset, withdrawal, or end of 2019. IS was defined by ICD codes (≥2 outpatient visits or 1 hospitalization). Multivariable-adjusted Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI). Kaplan-Meier analysis compared cumulative incidence.

**Key Results:** The blepharitis cohort was 61.62% female, mean age 52.09±17.77 years, mean follow-up 7.02±3.32 years. During follow-up, 27,108 (6.40%) blepharitis patients developed IS versus 20,804 (4.90%) controls (incidence rate 9.10 vs 7.00 per 10,000 person-years). Blepharitis was associated with significantly increased IS risk (adjusted HR [aHR] 1.32, 95% CI 1.29–1.34, p<0.001). Male sex (aHR 1.17, 95% CI 1.15–1.19, p<0.001) and age ≥60 (aHR 22.04 vs age 20–39, 95% CI 20.73–23.43, p<0.001) were also significant risk factors. Stratified analysis showed the blepharitis-IS association was stronger in patients with malignancy (aHR 1.51 vs 1.31, p for interaction <0.0001). The risk was highest within the first year after blepharitis diagnosis (aHR 1.41, 95% CI 1.35–1.46, p<0.001) and remained significant after >6 years (aHR 1.17, 95% CI 1.12–1.22, p<0.001). Kaplan-Meier curves showed significantly higher cumulative IS incidence in the blepharitis group over 10 years (log-rank p<0.001).

**Clinical Implications:** This large population-based study provides the first epidemiologic evidence that blepharitis is associated with a 32% increased risk of ischemic stroke, independent of traditional stroke risk factors. The elevated risk persists for over 6 years, with the highest risk in the first year. These findings suggest that blepharitis may be an independent risk factor for IS, possibly through systemic inflammation, infection, and secondary coagulopathy. The authors recommend early treatment and active surveillance for patients with chronic blepharitis, and suggest that ophthalmologists and neurologists consider the potential for IS in these patients. Limitations include the retrospective design, potential misclassification from diagnostic codes, inability to assess blepharitis severity, and residual confounding. Prospective studies with inflammatory markers are needed to validate these findings and elucidate causal mechanisms.