The mechanism of radiation injury has been well described for soft tissue and bone,^{56,67,70,72,73,89,90,104} but little research has been done on neural tissue. Three principal mechanisms have been suggested for the development of brain radionecrosis.

A. Inflammatory Response Initiated in Brain
The first is that damage to cerebral white matter is the result of uncontrolled cerebral edema; radiation exposure to the brain initiates an inflammatory response that produces permeability changes in the blood brain barrier.^46,60,61,100 This hyperpermeability leads to cerebral edema⁷ which is the first pathologic finding consistently observed.⁸³ The edema causes elevated intracerebral pressure at the injury location,^9,18,20,65 which then compromises blood flow. This compromised blood flow results in hypoxia, infarction and white matter necrosis.⁸³

B. Direct Damage to Endothelial Cells
A second mechanism suggests that vascular flow is reduced by a direct microvascular injury causing infarction and necrosis; direct damage to endothelial cells is common and fibrinoid necrosis of the small arteries and arterioles ensues.¹⁰⁰ The injury may lead to an occlusive arterial cerebrovasculopathy and necrosis.¹ Additionally, edema is a side effect of this injury and may result in damage through the previous pathway.

C. Demyelination of Oligodendrocytes
The third possible mechanism suggests that proliferating oligodendrocytes are directly affected by radiation, resulting in demyelination, reactive gliosis, and coagulation necrosis.^{37,46,57,60,100} Cerebral edema also ensues as a result of this injury. MRI commonly shows lesion enlargement, progressive enhancement, and edema.³⁰ The evolution is thought to relate to intralesional reactions and perilesional edema and demyelination.¹⁰⁰ The three injury pathways are illustrated in Figure 1 above.

Figure 1. Possible mechanisms of injury in brain radionecrosis.
ENLARGE

The postulated injury mechanism for brain radionecrosis only differs to that found in bone and other soft tissue by the presence of edema. The radiation injury is similar in that hypoxic, hypovascular, necrotic lesions develop. The brain develops a diffuse injury pattern that produces shallow oxygen gradients between damaged and healthy tissue. This shallow oxygen gradient inhibits angiogenesis and the damaged tissue cannot be revascularized. While the injury pattern in brain radionecrosis and radionecrosis of bone and soft tissue is similar, current treatment modalities differ greatly. In brain radionecrosis, conventional treatment has focused on controlling edema and not on promoting angiogenesis and revascularization of the injured tissue.