Fractionated stereotactic radiosurgery in rat brain: histopathological determination of dose-response and tolerance

Fractionated stereotactic radiosurgery (fSRS) allows single or multiple high dosage radiation of small volumes within the brain, i.e. addressing intracranial tumors. Reasonable protection of perilesional brain parenchyma raises clinical interest in fSRS strategies and promising results were already achieved for numerous focal lesions (e.g.: arteriovenous malformations, brain metastases, small benign tumors and malignancies). The effect of hyperfractionated stereotactic radiosurgery on healthy brain tissue (e.g.: apoptosis, necrosis, impact on the blood-brain-barrier) remains, however, to be determined.

Adult male Wistar rats underwent MRI and CT scanning of the brain and respective coordinates were introduced to a NOVALIS (BrainLab, Munich) fSRS device. All animals (body weight 350g) were irradiated with doses of 20 (n=3 animals), 30 (n=3 animals) and 40 Gy (n=3 animals) targeted to the left hippocampus. Animals were sacrificed 8, 12 and 16 weeks after fSRS and brains were immersion fixed in 4% paraformaldehyde for subsequent histopathological analysis. Coronal HE-stained sections of the brain were matched with coronal MRI and CT reconstructions and isodose distributions of fSRS. In concordance with isodose distributions, pathological signal hyperintensities were recorded from T2-weighted MRI scans following 4×10 Gy after 8 weeks, and 3×10 Gy after 12 weeks while 2×10 Gy induced no detectable alteration. Subsequent histopathological analysis revealed hippocampal cell loss in CA1 pyramidal cell layers as well as dentate granule cells in animals treated with 30 and 40 Gy. In conclusion, partial brain irradiation with fSRS in small animals was succesful for the first time and confirms its accuracy. This approach can be further developed for quality assurance in fSRS treatment of normal tissue or orthotopic tumor models.