Disseminated necrotizing leukoencephalopathy: A complication of treated central nervous system leukemia and lymphoma

Abstract

This report describes a form of disseminated necrotizing leukoencephalopathy that has been observed in four children with acute lymphoblastic leukemia, and one child with Burkitt's lymphoma terminating in a leukemic phase. In addition to systemic vincristine, cytosine arabinoside, cyclophosphamide, and steroids, these patients received courses of intrathecal methotrexate, cytosine arabinoside, and hydrocortisone, because of meningeal tumor cell infiltration. Whole brain radiation was also given either before or during intrathecal therapy. Three of the children had a progressive irreversible neurologic illness, which developed either at or shortly after the completion of combined triple intrathecal therapy, death ensuing approximately 2 months later. The neuro‐pathologic lesions consisted of discrete multifocal necroses of coagulative type, apparently extending by confluence, and disseminated in the cerebral white matter in a random manner. In one case, extensive symmetrical demyelinating and necrotizing lesions involved the centrum ovale bilaterally. There was a remarkable absence of inflammatory cellular response and a relative paucity of macrophage reaction, with usually little or no tissue breakdown. In addition to demyelination and glial cell loss, there was striking axonal damage, with conspicuous axonal swellings both within and around the necrotizing lesions. The surrounding white matter showed focal status spongiosus and a moderate astrocytic response. Vascular fibrinoid necrosis was inconstant and, except in one case, rarely observed. The possible causal relationship of these lesions to combined triple intrathecal antimetabolite therapy and brain radiation is discussed.

Lesions of the central nervous system in leukemia: Pathological and magnetic resonance imaging features at presentation in 14 patients

“…However, as well as CNS radiation therapy (31), this contributes to neurotoxicities. Examples of neurotoxicity include leukoencephalopathy and spontaneous intracranial hemorrhage (11,(32)(33)(34). Infection may be caused by leukemia itself, as well as the bone marrow suppression observed with intense chemotherapy (13).…”

“…The diagnosis of CNS leukemia should be considered in the differential diagnosis of patients with leukemia and CNS lesions, including those with CNS infection and neurodegenerative disorders following leukemia treatment. CNS lesions in leukemia may occur due to the disease itself, or the treatment (8)(9)(10)(11)(12)(13). Disease-associated CNS complications may consist of leukemic cell involvement of the meninges, parenchyma, and cerebrovasculature (8), whilst treatment-associated CNS complications may include leukoencephalopathy, inflammatory demyelinating polyradiculoneuropathy, infections, vascular disorders and secondary tumors (9)(10)(11)(12).…”

Leukoencephalopathy and Cortical Laminar Necrosis Associated with Intrathecal Methotrexate and Cranial Irradiation

“…3 Delayed necrotizing leukoencephalopathy, a complication of leukemia treatment, may occur after intrathecal, 1 intraventricular, 7 or high-dose intravenous treatment with MTX 8 in combination with 5-fluorouracil and is seen mostly in patients who have received concomitant cranial irradiation. 8 The exact mechanism of MTX-induced neurotoxicity remains unclear. It is likely multifactorial.…”

Early CNS toxicity after intrathecal methotrexate

“…Both high-dose intravenous MTX and intrathecal MTX are proposed to have association with demyelination, white matter necrosis, loss of oligodendroglia, axonal swelling, microcystic encephalomalacia, and atrophy relatively selective for the deep cerebral white matter [2]. An altered myelin metabolism disturbance induced by [3] or elevated levels of homocysteine and its excitatory amino acid neurotransmitter metabolites (homocysteic acid and cysteine sulfi nic acid) may mediate, in part, methotrexate-associated neurotoxicity [4].…”