Antimetabolites

METHOTREXATE

Methotrexate is a competitive inhibitor of dihydrofolate reductase, acting primarily during DNA synthesis (S-phase) as an antifolate antineoplastic drug. It prevents two primary reactions, the conversion of folic acid to tetrahydrofolic acid and the conversion of tetrahydrofolic acid to folinic acid, therefore blocking DNA, RNA, and protein synthesis by limiting the availability of reduced folates. [1 , y , y As an oral or intravenous drug in the usual prescribed doses, methotrexate is a neurologically safe agent. It has limited ability to cross the blood-brain barrier, and the CSF concentration is less than 10 percent of that in plasma after oral or parenteral administration. When given intrathecally or in higher doses, however, methotrexate is associated with a number of neurological syndromes. Proposed mechanisms of methotrexate neurotoxicity include depletion of cerebral reduced folates, reduced cerebral protein, altered blood-brain barrier permeability, and impaired neurotransmitter synthesis.y The risk of neurotoxicity is increased with increasing total intrathecal methotrexate dose, prolonged elevated CSF methotrexate levels, concurrent radiation therapy, or systemic high-dose methotrexate therapy. Toxicity is also more frequent and severe in younger patients

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and when methotrexate is used as treatment for meningeal tumor rather than for prophylaxis. y

Acute methotrexate neurotoxicity includes an acute chemical meningitis with fever, headache, nuchal rigidity, and CSF leukocytosis. This condition is usually mild to moderate; begins within hours of intrathecal administration; lasts for 1 to 3 days, although it may persist for 2 weeks; resolves spontaneously; and does not recur with subsequent therapy.'j' , y , y An acute strokelike encephalopathy with seizures, confusion, hemiparesis, and coma may complicate high-dose methotrexate (more than 1 g/m2 ) in as many as 15 percent of patients. y Other acute complications that occur within hours of intrathecal administration are acute transverse myelopathy with paraplegia, which may be permanent, and transient radiculopathies, possibly related to epidural or subdural injection, or the development of hematomas. y , '50' Accidental intrathecal methotrexate overdose may produce an ascending myelopathy and necrotizing leukoencephalopathy. y Doses of 50 mg or less probably produce few serious sequelae. A moderate overdose (50 to 100 mg) without early cSf drainage may produce an acute chemical meningitis. Massive overdose (more than 500 mg) causes myelopathy and encephalopathy, which may be fatal. Intensive systemic support, high-dose leucovorin, and alkaline diuresis, plus rapid CSF drainage and ventriculolumbar perfusion, may permit survival and recovery of neurological function.

Delayed neurotoxicity from repeated intrathecal or intraventricular methotrexate is more frequent than acute intoxication, and encephalopathy is the most important late effect. Pathologically, this is a leukoencephalopathy, with areas of coagulative necrosis, demyelination, and mineralizing microangiopathy. Clinically, it is characterized by progressive personality and intellectual decline, dementia, hemiparesis, and sometimes seizures. MRI and CT usually show extensive, patchy white matter lesions. The long-term effects of the treatment (or prophylaxis) of childhood leukemia and brain tumor include behavioral changes, poor school performance, memory loss, intellectual decline, growth retardation, hormonal disturbances, and abnormal CT scans. Although radiotherapy may account for many of these complications, intrathecal methotrexate alone may produce intellectual and behavioral problems or exacerbate those produced by radiotherapy. y

5-FLUOROURACIL

5-Fluorouracil is a fluorine-substituted analog of the pyrimidine uracil. It inhibits the enzyme thymidylate synthetase, blocking DNA synthesis by reducing thymidine monophosphate formation. It is associated with a characteristic cerebellar syndrome in 1 percent of patients when the recommended doses are used. When doses exceed the usual recommendations, the incidence of this cerebellar syndrome may be as high as 3 to 7 percent. The mechanism of 5-fluorouracil neurotoxicity is unknown, but its conversion to fluocitrate and fluoacetate in the CNS with subsequent inhibition of the Krebs cycle has been postulated. y , y , y Concomitant administration of alpha-interferon, cisplatin, leukovorin, or thymidine potentiates the toxic effects. y

Clinically, 5-fluorouracil induces pancerebeller dysfunction, characterized by the acute or subacute onset of gait ataxia, limb incoordination, dysarthria, nystagmus, and, sometimes, diplopia. The symptoms are usually controlled by dose reduction or increase in intervals between treatments. Although the syndrome is reversible, cases of re-emergence after subsequent treatment have been reported. y , '50' , '51'

Other neurotoxic reactions associated with 5-fluorouracil include encephalopathy, as well as a parkinsonian syndrome in 40 percent of patients. '51' The encephalopathy is usually mild to moderate but can range from lethargy to coma with high-dose infusions. All of the neurological symptoms associated with 5-fluorouracil are usually reversible on cessation of the drug, and no pathological changes have been noted in the brain at postmortem examination. '51'

CYTOSINE ARABINOSIDE (CYTARABINE)

Cytosine arabinoside is an analog of pyrimidine nucleosides and readily crosses the blood-brain barrier. The drug destroys proliferating cells as an S-phase-specific cytotoxic agent. In many animals, in which cellular proliferation is active in the external granular layer of the cerebellum, cytosine arabinoside selectively destroys this layer and causes disarrangement and abnormal arborization of the Purkinje cells. y

Although the drug has little neurotoxicity following usual intravenous doses, in high doses it can cause an acute cerebellar syndrome in up to 14 percent and less commonly seizures and encephalopathy. When given intrathecally, it may result in myelopathy or cauda equina syndrome that is incompletely reversible. Combined intrathecal cytarabine and cranial irradiation may lead to necrotizing encephalopathy. Intravenous therapy may cause a peripheral neuropathy. y The incidence and severity of neurotoxicity increases with increasing dose (more than 18 g/m2 /course), increasing age (being rare in patients younger than 20 years of age, occurring in 3 percent of those from 20 to 50 years of age, and in 19 percent of those older than 50 years of age), and following subsequent rather than initial courses. y Symptoms of neurotoxicity typically begin 6 to 8 days after the initiation of cytosine arabinoside with nystagmus and ataxia, peak over the following 2 to 3 days (confusion, somnolence, ataxia, dysarthria, and sometimes seizures or coma), start to improve within 1 week, and resolve completely within 2 weeks in most patients.y Cerebellar atrophy may be seen on CT or MRI, and pathological changes are remarkable for Purkinje cell loss, reactive Bergmann's gliosis, and occasionally, demyelination.

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