Multifocal inflammatory leukoencephalopathy with 5‐fluorouracil and levamisole

Abstract

A cerebral demyelinating disease developed in 3 patients during adjuvant therapy with 5-fluorouracil and levamisole for adenocarcinoma of the colon. None of the patients had evidence of metastatic disease or prior neurological disease. The duration of chemotherapy before onset of neurological symptoms ranged from 15 to 19 weeks. The total dose of 5-fluorouracil was 9.7 to 15.7 gm. The total dose of levamisole was 2.7 to 3.75 gm. Two patients presented with a subacute (2-3 weeks) progressive decline in mental status and ataxia. The third patient had two unexplained episodes of loss of consciousness. In each, magnetic resonance imaging with gadolinium demonstrated prominent multifocal enhancing white matter lesions. Cerebral biopsy was performed stereotaxically in 2 patients. The morphological features were those of active demyelinating disease. The myelin loss was associated with numerous dispersed as well as vasocentric macrophages, sparing of axons, and perivascular lymphocytic inflammation. Electron microscopy confirmed the light microscopic findings. All 3 patients improved after cessation of chemotherapy and a short course of corticosteroid therapy. Our patients represent the first reported examples of an inflammatory leukoencephalopathy associated with the administration of 5-fluorouracil and levamisole. This syndrome may represent the pathological basis for 5-fluorouracil neurotoxicity, although we cannot completely exclude the role of levamisole.

Case Files of the New York City Poison Control Center: Paradichlorobenzene-Induced Leukoencephalopathy

“…In addition, risk for encephalopathy increases appreciably when chemotherapeutic agents are added to radiation regimens. White matter pathology ranges from radiologically detectable asymptomatic disease to a fatal necrotizing leukoencephalopathy [27][28][29]. RPLS is associated with an increasing number of anticancer drugs.…”

Reversible posterior leukoencephalopathy syndrome associated with mFOLFOX6 chemotherapy

“…Although the possibility that RPLS might have developed as a result of the vascular endothelial toxicity of 5-fluorouracil cannot be completely ruled out, the cerebral toxicity of 5-fluorouracil is well-described as a multifocal inflammatory leukoencephalopathy. Multifocal inflammatory leukoencephalopathy typically develops 6 weeks to 5 months after the initiation of chemotherapy, and is a clinically and radiographically distinct syndrome from RPLS, making it unlikely that 5-fluorouracil was the cause of the RPLS in this patient [24,25]. Therefore, we hypothesize that platinuminduced vasculoendothelial damage in our patient led to RPLS development.…”

5-FU multifocal inflammatory leukoencephalopathy and dihydropyrimidine dehydrogenase deficiency

“…There have been several case reports of MIL since it was first clearly described in 1992. 2 This uncommon but increasingly clinically important syndrome is characterized by the gradual onset of multiple neurologic deficits, which can include confusion, ataxia, parasthesias, focal weakness, coma, and death. Symptoms generally develop 6 weeks to 5 months after initiation of combination chemotherapy with levamisole and 5-FU.…”

“…3 Pathologic tissue examination reveals demyelination with relative axon sparing. 2,4 Symptoms resolve both with and without therapy, with therapy typically consisting of a short course of corticosteroids. 2,5 The vast majority of case reports describing MIL are associated with 5-FU and levamisole in combination.…”

“…2,4 Symptoms resolve both with and without therapy, with therapy typically consisting of a short course of corticosteroids. 2,5 The vast majority of case reports describing MIL are associated with 5-FU and levamisole in combination. 3 However, a single case occurred after administration of levamisole alone, 5 and another patient improved after discontinuation of levamisole despite continuation of 5-FU.…”