Table 6.
Neurological and cerebrovascular effects of repeated intravitreal anti-VEGF therapy
| Author, year | Type of study | Anti-VEGF agent(s) | Results | Inference |
|---|---|---|---|---|
| Starr et al. 2019 [59] | Retrospective study with 2-year follow-up; control group with no anti-VEGF injections | Not specified | 5.8% had stroke post anti-VEGF; 71.1% ischemic, 15.8% embolic, 13.2% hemorrhagic; stroke types similar to control group | No increased stroke subtype risk due to anti-VEGF; no predilection toward infarcts or hemorrhages |
| Dalvin et al. 2019 [60] | Population-based retrospective cohort study (2004–2013) in exudative ARMD patients | Pegaptanib, bevacizumab, ranibizumab, aflibercept | No increased stroke risk in anti-VEGF group versus controls | Intravitreal anti-VEGF not linked to increased stroke risk in ARMD |
| Sultana et al. 2020 [61] | Retrospective review of individual case safety records (ICSRs) for anti-VEGF drugs (2010–2016) | Bevacizumab, ranibizumab, pegaptanib, aflibercept | 59.88% of ICSRs from > 65 y/o; potential signal linking intravitreal ranibizumab with Parkinson’s disease | VEGF inhibition might impair neural signalling and plasticity, potentially contributing to Parkinson’s disease |
| Chen et al. 2021 [51] | Population-based retrospective study comparing patients with stroke/MI who received versus did not receive anti-VEGF | Not specified | Higher mortality in IVI group, especially if injections given within 1 year of MI/stroke | Increased mortality risk with anti-VEGF in patients with recent stroke/MI |
| Yoshimoto et al. 2021 [62] | Case report of 70-year-old male with DME | Aflibercept | Hypertensive cerebral hemorrhage 1-month post-bilateral injections; plasma VEGF dropped below detection and remained low for 2 months; recovered to 41 pg/ml after 2 months | Persistent VEGF suppression can trigger hypertension and cerebral hemorrhage; caution in elderly with comorbidities |
| Ray et al. 2021 [57] | Prospective study of ARMD patients (age 65–85); used iPad-based brain health test versus injection number | Not specified | > 20 injections linked with increased risk of mild cognitive impairment | Possible cumulative effect of anti-VEGF on cognitive function; brain health monitoring may be warranted |
| Fugara et al. 2022 [63] | Prospective study of diabetic patients: laser/conservative (Ggroup 1) versus anti-VEGF (group 2) | Bevacizumab | Non-arteritic ischemic optic neuropathy (NAION) more common in group 2, especially with ≥ 3 injections | Repeated bevacizumab may increase NAION risk in diabetic eyes |
| Yang et al. 2025 [57] | Pharmacovigilance study using VigiBase for cardiovascular/cerebrovascular ADRs with anti-VEGF | Ranibizumab, bevacizumab, aflibercept | Higher reporting of cerebral infarction, carotid stenosis, cerebral and subarachnoid hemorrhage; underreporting with aflibercept; higher rates with ranibizumab | Intravitreal anti-VEGF associated with cerebrovascular ADRs; ranibizumab showed higher cerebrovascular ADR reports than other agents |
IVI intravitreal injection, DME diabetic macular edema, ARMD age-related macular degeneration, ICSR individual case safety record, ADRs adverse drug reactions, NAION non-arteritic ischemic optic neuropathy, VEGF vascular endothelial growth factor, MI myocardial infarction