Pathogenesis of Central Nervous System Toxicity

Radiation

• Altered capillary wall permeability, resulting in alterations in cerebral blood flow

• Primary damage to glial cells, especially oligodendroglia

• Demyelination of glial tissue

• Focal white matter destruction

• Impaired neuronal differentiation, including dendritic formation and synapto-genesis.

Chemotherapy

The pathogenesis of chemotherapy-induced central nervous system (CNS) toxicity is not well understood. In addition to damage to the glial and capillary tissue, the neu-rotransmitter function of the brain may also be impaired.

With current trends in the use of higher doses of methotrexate, as well as the increased frequency with which methotrexate is used in intrathecal therapy, induced neurologic sequelae have been on the rise.

The four pathologic effects of prophylactic CNS therapy in leukemia are:

1. Leukoencephalopathy

2. Mineralizing microangiopathy

3. Subacute necrotizing leukomyelopathy

4. Brain tumors (second malignant neoplasm).

Leukoencephalopathy

• Clinical manifestations: seizure, ataxia, lethargy, slurred speech, spasticity, dys-phagia, lowered IQ scores, memory impairment, and confusion

• Onset of symptoms: usually 4 months after cranial radiation

• Radioimaging findings: dilatation of the ventricles and subarachnoid space, indicative of cerebral atrophy; white matter hypodensity by CT scan and hyperdensity on magnetic resonance imaging (MRI) indicative of leukoencephalopathy

• Correlation with treatment: 20-Gy cranial RT and use of both intratheal (IT) methotrexate (MTX) and systemic MTX (>40 mg/m2 weekly). This combination of therapy is most neurotoxic.

With the use of current treatments, this severe form of leukoencephalopathy is seen infrequently. The subclinical form of leukoencephaly is more common, characterized by radiologic abnormalities on CT scan and MRI without clinical symptoms. It occurs in approximately 55-60% of patients receiving CNS prophylaxis. Nonirradiated patients generally do not show both white matter changes (i.e., low-density areas) and gray matter changes (widening of sulci and ventricles). This combination of findings is seen more often in patients treated with cranial radiation, IT MTX, and systemic MTX.

Mineralizing Microangiopathy

• Clinical manifestations: seizures, electroencephalogram (EEG) abnormalities, incoordination, gait abnormalities, memory deficits, learning disabilities, decrease in IQ scores, behavioral problems

• Onset of symptoms: 10 months to several years after CNS prophylaxis (the risk of these complications increases proportionately with higher doses of IT MTX and irradiation combined with systemic chemotherapy. Irradiation is the main cause of this complication).

• Radioimaging findings: changes primarily in the gray matter of the brain mainly in the region of basal ganglia and less frequently in the cerebellar gray matter.

Histologically, there is deposition of calcium in the small blood vessels, causing lumen occlusion by mineralized debris. There may be dystrophic calcification of the surrounding neural tissue.

Subacute Necrotizing Leukomyelopathy

This unusual complication occurs after the use of cranial or craniospinal irradiation combined with IT MTX. Histologically, it shows focal myelin necrosis on the posterior and/or lateral columns of the spinal cord.

Brain Tumors (Second Malignant Neoplasm)

Patients with ALL who are younger than 5 years of age at the time of cranial irradiation are at a 1% risk to develop brain tumors within the first 10 years after therapy. Children treated under 6 years of age have an increased risk of developing high-grade gliomas. They are at risk for developing meningioma 10-20 years after cranial irradiation.

Children treated before 5-6 years of age, especially those treated before 3 years of age, are at a higher risk for developing cognitive impairments than those treated after the age of 8-10 years. Table 27-7 lists the clinical manifestations of neurotoxicity associated with irradiation therapy, and Table 27-8 lists the neurologic complications secondary to chemotherapy.

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