Administered in conventional oral or intravenous doses, methotrexate (MTX) is not usually neurotoxic. However, given intrathecally to treat meningeal leukemia or carcinomatosis, MTX commonly causes aseptic meningitis, with headache, nausea and vomiting, stiff neck, fever, and cells in the spinal fluid. Very rarely, probably as an idiosyncratic response to the drug, intrathecal administration results in an acute paraplegia that may be permanent. The pathology of this condition has not been studied.
The most serious and more common of the neurologic problems associated with systemic MTX chemotherapy is leukoencephalopathy or leukomyelopathy, especially when it is given in combination with cranial or neuraxis radiation therapy. This develops several months after repeated intrathecal or high systemic doses of the drug, and a few milder cases are known to have occurred without radiation treatments, that is, with oral or intravenous MTX alone, such as the case reported by Worthley and McNeil. We have seen one such instance in a woman receiving oral MTX for a systemic vasculitis; no alternative explanation for widespread white matter changes and mild dementia could be discerned. Nonetheless, this must be quite uncommon. The full-blown syndrome consists of the insidious evolution of dementia, pseudobulbar palsy, ataxia, focal cerebral cortical deficits, or paraplegia. Milder cases show only radiographic evidence of a change in signal intensity in the posterior cerebral white matter (“posterior leukoencephalopathy”) that is similar to the imaging findings that follow cyclosporine use (see further on) and hypertensive encephalopathy (Fig. 41-2). In severe cases, the brain shows disseminated foci of coagulation necrosis of white matter, usually periventricular, which can be detected with CT and MRI.
Mineralizing microangiopathy (fibrosis and calcification of small vessels, mainly in the basal ganglia) is yet another complication of MTX therapy. It may occur with MTX treatment or with cranial irradiation but is particularly common when both forms of treatment are combined. The present authors have the impression that the severe necrotic lesions possess features comparable to (and therefore may be the result of) the coagulative necrosis of radiation encephalopathy.
The Nitrosoureas
Carmustine (BCNU) and lomustine (CCNU) are nitrosoureas used to treat malignant cerebral gliomas. They are not neurotoxic when given in conventional intravenous doses, but intracarotid injection of the drugs may cause orbital, eye, and neck pain, focal seizures, confusion, and possibly focal neurologic deficits. Postmortem examinations of patients who had been treated with intravascular BCNU have disclosed a diffuse vasculopathy characterized by fibrinoid necrosis and microthrombi and diffuse foci of swollen axis cylinders and myelin vacuolization (Burger et al; Kleinschmidt-de Masters).