Neurotoxicity Due to CNS Therapy for Leukemia

Abstract

CNS symptoms ranging from mild to lethal have occurred following CNS radiotherapy and intrathecal chemotherapy. Cranial radiotherapy often produces signs of mild encephalopathy, with predominance of somnolence. In rare cases, it appears that CNS radiotherapy may be followed by progressive encephalopathy. Intrathecal methotrexate frequently causes symptoms of meningeal irritation. Occasionally cases of weakness and paralysis, and rare instances of severe encephalopathy, may occur. However, in leukemic children treated with intensive chemotherapy and CNS radiotherapy who develop neurological complications, it is often difficult to determine which of many possible factors may be causing the CNS symptoms. The pathogenesis of the various forms of methotrexate neurotoxicity is poorly understood. The best-established cause for these symptoms is high concentrations of methotrexate in the CSF or porlonged exposure of the brain to low CSF concentrations of methotrexate. These elevated concentrations of the drug may in turn be due to impaired elimination of the drug from the cerebrospinal fluid (usually due to overt CNS leukemia) or to increased dosage in relation to cerebrospinal fluid volume (due to adolescent age). Leukoencephalopathy is occasionally found at autopsy in children given intensive therapy with CNS radiotherapy and intrathecal methotrexate, together with intensive systemic chemotherapy. It was proposed that alteration of the blood-brain barrier by cranial radiotherapy allows systemically administered anti-leukemic drugs to enter the brain and to cause necrotic changes in the CNS white matter. Leukoencephalopathy also occurs following intraventricular administration of methotrexate. CNS-toxicity due to intrathecal cytosine arabinoside is clinically similar to the symptoms seen following intrathecal methotrexate.

Cerebellar herniation after intrathecal chemotherapy including cytosine arabinoside in a boy with T acute lymphoblastic leukemia

“…1 On the basis of the impressive results obtained in the pilot trial of the Memorial Sloan-Kettering Cancer Center, 2 92% complete remission (CR) rate in relapsed APL patients, in the United States a multicenter study has been conducted to evaluate the efficacy and tolerability of As 2 O 3 for remission induction and consolidation in a larger population of APL patients who had relapsed from prior retinoic and anthracycline-based chemotherapy. 3 In this study the authors reported an 85% CR rate with a relapse free survival rate at 18 months of 56%.…”

“…Leukemia neurotoxicity. [2][3] The CSF clearance of ara-C is similar to that of the CSF bulk flow rate. Furthermore, there is little conversion of ara-C to uracile arabinoside in the brain and CSF.…”

“…Signs of meningitis such as nuchal rigidity and photophobia were present but no papilledema was noted. CSF analysis revealed 1270 blast cells/mm 3 . Computed tomography (CT) of the CNS performed 12 h after lumbar puncture showed a normal CNS parenchyma without any evidence of tumour infiltration and cerebellar tonsils in normal location (Figure 1).…”

Sudden neurologic death after intrathecal methotrexate

“…It is known that patients who tend to develop MTX leukoencephalopathy are those who had active CNS involvement at the initiation of therapy [2,10,11]. Diagnostic tests to screen for subclinical progressive neurotoxicity would be valuable adjuncts in planning or altering CNS therapy.…”

“…Three major syndromes have been described: meningeal irritatiodarachnoiditis , paraplegia, and encephalopathy [2,11]. The leukoencephalopathy syndrome is manifested by chronic progressive confusion, poor school performance, somnolence, tremor, ataxia, and dementia.…”