Mecobalamin Combined With Anti-VEGF Intravitreal Injection for Treatment Retinal Vein Occlusion: a Double-blind Randomized Controlled Trial

Retinal vein occlusion (RVO) is the second leading cause of vision loss resulting from retinal vascular disease, with a prevalence of approximately 0.6%-1.6%. Macular edema (ME) secondary to RVO is a common cause of vision loss. RVO induces hypoxia and ischemia, leading to neuronal loss and increased vascular permeability. Therefore, anti-vascular endothelial growth factor (anti-VEGF) injections are widely used as first-line treatment for RVO-ME, achieving remarkable therapeutic effects. Pivotal trials (BRAVO and CRUISE) demonstrated that anti-VEGF therapy significantly improves best-corrected visual acuity (BCVA) and reduces retinal swelling, enhancing BCVA by 12-15 ETDRS letters and decreasing central foveal thickness (CFT) by about 200 μm.

However, therapies targeting VEGF alone may not sufficiently manage this condition. Although anti-VEGF agents improve edema and short-term visual acuity, long-term efficacy is limited by frequent injections and inadequate nerve repair. Additionally, anti-VEGF fails to reverse neurodegenerative changes such as photoreceptor apoptosis and Müller cell activation. Consequently, combined strategies synchronizing vascular leakage repair and neuroprotection have become an international research priority.

As a typical neurotrophic drug, mecobalamin repairs nerve tissue and accelerates axonal regeneration and myelination. Mecobalamin, a vitamin B12 derivative, is more readily absorbed by nerve cells than vitamin B12 itself. As a methyl donor, it facilitates homocysteine-to-methionine conversion, supporting nucleic acid, protein, and phospholipid synthesis critical for myelin formation. This process is essential for nerve myelin formation and repair. Mecobalamin accelerates lipid, protein, and nucleic acid metabolism in neurons, enhancing nerve function recovery and alleviating neurological symptoms. Previous studies found that oral vitamin B1 and mecobalamin improve corneal nerve fiber density. The neuroprotective drug was shown to attenuate oxidative stress in animal models, but clinical translation evidence remains insufficient.

Notably, VEGF exhibits dual roles as both a permeability factor and neuroprotectant. Excessive VEGF inhibition may exacerbate retinal ganglion cell apoptosis. Although mecobalamin promotes neural repair, its spatiotemporal synergy with anti-VEGF in neurovascular unit (NVU) recovery remains uncharacterized. This prospective, double-blind, randomized controlled trial evaluates the synergistic effects of mecobalamin combined with anti-VEGF therapy on NVU repair in RVO-ME, utilizing dual-targeted "vascular intervention + neuroprotection" to overcome current limitations.

Current ME efficacy assessment relies primarily on optical coherence tomography (OCT)-derived CFT, with few tertiary centers employing OCT angiography (OCTA), multifocal electroretinography (mfERG), or adaptive optics (AO). Existing metrics inadequately characterize NVU function or anti-VEGF effects on non-vascular components (glia, photoreceptors). The absence of standardized NVU repair quantification impedes cross-study comparisons. To address this, the investigators propose a multimodal "OCT structural tomography + OCTA flow stratification + AO cellular morphology + microperimetry functional mapping + mfERG functional localization" assessment to establish a new therapeutic standard.