Leukoencephalopathy following combined intrathecal methotrexate and cranial irradiation (see further on, under “Radiation Toxicity”) Cranial radiation, combined with methotrexate given intrathecally or intravenously, has been effective in the prevention and treatment of meningeal involvement in childhood leukemia. However, in a significant number of patients this combination gives rise to a distinctive acute necrotizing leukoencephalopathy within several days to weeks after the last administration of methotrexate (Robain et al). This condition has been distinguished from the more conventional form of cerebral radiation necrosis discussed later. The leukoencephalopathy occurs most frequently and is most severe when all three modalities of treatment, that is, cranial irradiation and intrathecal and intravenous methotrexate, are used in children. The age differentiation may explain the infrequency of this condition in adults. The initial symptoms—consisting of apathy, drowsiness, depression of consciousness, and behavioral disorders—evolve over a few weeks to include cerebellar ataxia, spasticity, pseudobulbar palsy, extrapyramidal motor abnormalities, and akinetic mutism.
In the acute and fulminant form of the disorder, large hypodense areas of varying size appear on CT and there can be contrast enhancement and edema that may simulate a tumor. This is distinct from the common occurrence of regional radiation change surrounding a tumor or sometimes distant to it. On MRI these lesions appear T2 hyperintense and can have poorly demarcated borders. In a few patients this aggressive form of the condition stabilizes or improves, with corresponding resolution of enhancement and edema. (The concept of “pseudoprogression” of a brain tumor has been introduced to denote radiation change that simulates tumor growth). More often, the patient is left with severe persistent sequelae or rarely the edema may progress and lead to death.
In addition to radiation injury, important factors in the development of the fulminant syndrome are the age of the patient (many are younger than 5 years old). In an attempt to address the long-term cognitive sequela of cranial radiation in children with leukemia, Pui and coworkers conducted a study and found that it could be safely omitted if all other aspects of therapy have been optimized.
Involvement of the Nervous System in Systemic Lymphoma
Extradural compression of the spinal cord or cauda equina is the most common neurologic complication of all types of lymphoma, the result of extension from vertebrae or paravertebral lymph nodes. Treatment is with radiation to the affected portion of the neuraxis or, if the compression is very acute and causing serious myelopathy, surgical decompression. Systemic lymphoma rarely metastasizes to the brain. In a review of more than 100 autopsies at the Mallory Institute of Pathology, our colleague R.D. Adams observed only a half-dozen instances where patients with lymphomas had deposits of tumor cells in the brain and in none of these cases were they from multiple myeloma (Sparling et al). In the series of Levitt and associates, comprising 592 patients with non-Hodgkin lymphoma, there were only 8 with intracerebral metastases.