The principal targets of radiation within the brain are the endothelial cells and the glial cells. The neurons themselves are relatively radioresistant as they rarely divide; neuronal stem cells and hippocampus neurons are a significant exception.
The late effects of radiation on the central nervous system are:
- Pseudoprogression
- Transient Demyelination (Lhermitte's sign)
- Radiation necrosis
- Neurocognitive effects
- Increased risk of stroke and haemorrhage
- Myelopathy of the spinal cord
These late effects are thought to arise from a complex interaction of damage between neurons, astrocytes, oligodendrocytes, microglia and endothelial cells.
Individual Cell Effects
Endothelial cells
Endothelial cells respond similarly in all body organs but can be modulated by cytokines released by nearby parenchymal cells. They have a delayed response to radiation, likely due to long periods between cell division. Histologically, capillaries may be lost due to cell death or dilate to form telangiectasia in response to ischaemia. The nuclei of endothelial cells may enlarge. Vessels are often hyalinised. Although intially thought to be the sole cause of radiation induced late effects, there is evidence that the endothelial and vessel changes are part of the overall effect of radiation.
Astrocytes
Astrocytes perform a vast number of roles within the CNS. They help to form the blood brain barrier together with endothelial cells and promote neurogenesis. Histological changes include hypertrophy of the cells and nuclei and an increase in GFAP expression. They contribute to the pathogenesis of late effects by releasing pro-inflammatory cytokines.
Oligodendrocytes
Oligodendrocytes provide myelination to neuronal axons. There is a transient loss of these cells and their stem cells from radiotherapy which contributes to transient demyelination syndromes between treatment and 6 months. Long term effects of radiation on this cell population are unclear and their role in late toxicity is uncertain.
Microglia
Microglial cells are differentiated macrophages that form about 10% of the cell population in the brain. They release growth signals and regulate inflammatory responses. In response to radiotherapy they become activated, more rounded, and begin proliferating. They release pro-inflammatory cytokines which encourage a long acting inflammatory response. Their exact role in late effects is also unclear.
Neurons
Neurons are not as resistant to radiotherapy as previously thought. There is evidence of reduced activity of neurons, particularly in the hippocampus, following radiotherapy which may explain neurocognitive effects. Neurons have different gene expressions following radiotherapy.
Summary
The exact mechanisms by which radiation necrosis develops are likely due to complex interactions of endothelial cells, astrocytes and perhaps microglia and oligodendrocytes. Radiation induced neurocognitive decline is likely due to radiation effects on neurons and astrocytes but other cells may have an undefined role.
Pathological Changes
Histological changes include:
- Demyelination (first few months)
- Enlargement and depletion of capillaries and small vessels (telangiectasia, loss of endothelial cells)
- Hyalinisation of vessel walls
- Activation of microglial cells (rounded, proliferation)
- Increased expression of GFAP by astrocytes
- Neuronal changes are only seen on gene expression studies or electric activity changes.
- Gliosis (proliferation of astrocytes)
- Necrosis
Dose and Time Effects
Radiation necrosis of the brain is rare with doses under 60 Gy. Point doses of 72 Gy are associated with a 5% risk of radiation necrosis.
Neurocognitive effects are difficult to test for and are probably under-reported. It is likely that lower doses of radiation can impact brain function, particularly memory. In children doses to the brain over 18 Gy as associated with neurocognitive impairment.
In the brainstem, similar changes are seen although dose limits are lower (< 54 Gy, point doses up to 59 Gy accepted).
The spinal cord is thought to be more radiosensitive and dose limits are lower again (< 50 Gy associated with 0.2% risk of myelopathy).
