Clinical and Histopathologic Effects of Radiotherapy on the Sciatic Nerve in a Rat Model

Abstract

Objective: Radiation-induced peripheral neuropathy (RIPN) is a debilitating effect of external beam radiation therapy, impacting 9-60% of treated patients. The exact pathogenesis and time to onset of RIPN are unknown, necessitating the creation of an animal model to explore radiation dose dependent sciatic nerve injuries. This study is aimed to (1) create a targeted radiation-induced sciatic nerve injury in a rat model and (2) analyze histological and functional impact across 3 radiation doses, 20/40/60 Gy, at 4-weeks and 16-weeks post-radiation. Methods: 18 male Lewis rats were equally split into three treatment groups of differing radiation dosages. The left thigh of each rat was irradiated while the right served as a control. Primary outcomes were measured with histologic findings based on necrotic and vascular changes, with secondary outcome measures including sciatic functional index, tibialis anterior muscle mass, sciatic nerve conduction velocity, axon count, and axonal swelling. Results: Overall, Sciatic Functional Index scores showed a decline in lower extremity function over time and a significant difference was found in the tibialis anterior muscle mass between the control and radiated sides (p<0.001). There was a significant difference in nerve conduction velocity between the control and irradiated sciatic nerves (p<0.0001), and for two of the dosage-specific subgroups. Furthermore, there was a significant difference in axon count per high powered field between the control and radiated sciatic nerves (p<0.001). Axonal swelling also significantly increased in the radiated side (p<0.001). Lastly, a significant difference was found in the severity of necrotic and vascular change between the control and irradiated sciatic nerves. Conclusion: This study illustrated the viability of radiating small animals with single-fraction external beam radiation up to 60 Gy. We believe these findings begin to provide an explanation for post-radiation symptoms that patients experience, and will lay the groundwork for future RIPN animal studies.