Brachytherapy using episcleral 125I seed-filled plaques is the standard treatment for uveal melanoma, the most common primary intraocular cancer in adults (Group, 2006). However, the multicenter Collaborative Ocular Melanoma Study (COMS) and other trials demonstrated that at least 50% of patients treated with brachytherapy experience significant vision loss within 3–5 yr after therapy (Group, 2006; Melia et al., 2001, 2006; Aziz et al., 2016; Shields et al., 2000). The COMS reported extensive pathology after 2 yr or more in the normal retinal tissue that surrounded the melanoma (Boldt et al., 2009). An accepted, but incompletely tested concept is that radiation retinopathy is driven by microangiopathy that is initiated by the immediate damage to the microvascular endothelium during radiation.

Despite observations in humans consistent with early microvascular leakage and loss of microvascular and neuronal density years after therapy, few animal studies have been conducted to establish the mechanisms of radiation retinopathy. Several animal studies have reported on pathology after radiation of the eye, including photoreceptor damage and capillary loss (Archer et al., 1991; Amoaku et al., 1989; Irvine and Wood, 1987). These studies were conducted in a variety of species such as monkey, pig, cat and rat (Singh et al., 2012; Gragoudas et al., 1979). However, they have important limitations. In most studies, the main readout was descriptive histology rather than quantification (Irvine and Wood, 1987; Archer et al., 1991). In others, the main readouts were only obtained once at the end of the study. Only a few studies used mice based on the notion that ocular complications of radiation therapy are subtle in mice. Of these studies, most examined tumor control as opposed to microvascular and neuronal injury of the normal retinal tissue (Sobrin et al., 2004; Murray et al., 1996).

Establishing the stages of radiation retinopathy in mice is a prerequisite for preclinical testing of potential treatments. The lack of these data in mice is a major obstacle to capitalizing on the many available genetic models that could inform on molecular pathways and cell type specific contributions. Of note, no specific preventive treatment for radiation retinopathy is currently available, in part because the molecular and cellular drivers of radiation retinopathy are not well understood. Anti-VEGF therapy in humans has gained traction in the field supported by reports of decreased vision loss and macular edema after scheduled injections (Shah et al., 2014; Shields et al., 2020). However, microvascular density or retinal thickness were not affected (Eandi et al., 2021).

To fill some of these gaps, we sought to establish vascular and neuronal pathology in mice after cranial irradiation, specifically, evidence for early vascular leakage and late rarefication as well as neuronal cell death by apoptosis. We also tested whether OCT and laser speckle flowgraphy, in vivo imaging techniques that have recently been used in humans to investigate radiation retinopathy, can be deployed to characterize radiation retinopathy in mice.