5-FU multifocal inflammatory leukoencephalopathy and dihydropyrimidine dehydrogenase deficiency
David A. Franco, MD; and
Harry S. Greenberg, MD
From the Department of Neurology, University of Michigan Medical Center, Ann Arbor.
Address correspondence and reprint requests to Dr. Harry S. Greenberg, Department of Neurology, University of Michigan Medical Center, Taubman Center 1914/0316, Ann Arbor, MI 48109; e-mail: hsgr{at}umich.edu
Multifocal inflammatory leukoencephalopathy (MIL) is a cerebraldemyelinating syndrome that develops after chemotherapy with5-fluorouracil (5-FU) and levamisole. The authors report a patientwho developed MIL after 5-FU administration not in associationwith levamisole. She was subsequently diagnosed with partialdeficiency of dihydropyrimidine dehydrogenase, an enzyme necessaryfor 5-FU catabolism. The authors suggest that MIL is a directresult of 5-FU chemotherapy and that patients with dihydropyrimidinedehydrogenase deficiency are at increased risk for this andother toxic effects of 5-FU.
Multifocal inflammatory leukoencephalopathy (MIL) is a raresyndrome associated with 5-fluorouracil (5-FU) and levamisolechemotherapy. The pathogenesis of MIL and the degree to whichit may be attributed to 5-FU or levamisole remain unclear. MILis reported in patients receiving 5-FU and levamisole in combinationor levamisole alone, but not 5-FU alone. We present a patientwho developed MIL and, subsequently, a partial dihydropyrimidinedehydrogenase (DPD) deficiency after administration of 5-FUand carboplatin.
A 65-year-old woman presented in December 1997 with sore throatand dysphagia. A neck CT showed an abnormal soft tissue densityin the region of the epiglottis. Subsequent biopsy revealedsquamous cell carcinoma of the epiglottis (T3, N1, M0). Chemotherapywas instituted August 6, 1998, with 700 mg/m2 of 5-FU IV dailyfor 5 days and a single bolus of 450 mg carboplatin IV. Thepatient received three cycles, with treatment ending September21, 1998.
During the first week of September 1998, the patient and herfamily noted gait and balance difficulties associated with frequentfalls. During the third cycle of chemotherapy, her family notedprogressive confusion, behavioral change, memory loss, and episodesof intermittent upper extremity paresthesias. Laboratory evaluationshowed electrolytes and liver function to be within normal limits.The patient’s symptoms improved gradually, returning tonormal by mid October 1998. Neurologic examination on October22, 1998, was normal except for mild gait ataxia, with the patientcompleting three of five serial seven calculations and recallingtwo of three objects at 5 minutes.
Brain MRI ( figure 1) 3 weeks after chemotherapy discontinuationon October 10, 1998, revealed multiple high-signal lesions onfluid attenuated inversion recovery (FLAIR) and T2-weightedimages. On T1-weighted images with gadolinium, there was contrastenhancement in several areas corresponding to T2-weighted abnormalities.A follow-up MRI ( figure 2) on December 16, 1998, showed amild decrease in the number of enhancing white matter lesionson T1-weighted postcontrast images and a stable appearance ofthe lesions on T2 and FLAIR images. The patient was clinicallyunchanged in January 1999.
Figure 2. T1-weighted MRI after gadolinium administration with several enhancing lesions on October 10, 1998 (A) and a reduction in the number of enhancing lesions by December 16, 1998 (B).
Testing for DPD deficiency was performed with urine and plasmauracil levels and direct serum enzymatic assay for dihydropyrimidinedehydrogenase. Plasma uracil measured 42.00 ng/mL, and urineuracil measured 44.478 ng/mL. Both values were within the normalrange. DPD assay was performed using previously described methods,with peripheral blood mononuclear cells isolated from a 60 mLwhole-blood sample.1 Analysis of the frozen (-70 °C) samplerevealed DPD activity to be 0.04500 nmol/min/mg protein, indicatinga partial enzyme deficiency ( table).
There have been several case reports of MIL since it was firstclearly described in 1992.2 This uncommon but increasingly clinicallyimportant syndrome is characterized by the gradual onset ofmultiple neurologic deficits, which can include confusion, ataxia,parasthesias, focal weakness, coma, and death. Symptoms generallydevelop 6 weeks to 5 months after initiation of combinationchemotherapy with levamisole and 5-FU. Brain MRI shows multiplewhite matter lesions without mass effect. Lesions are hyperintenseon T2-weighted imaging and may enhance on T1-weighted imagingafter gadolinium administration.3 Pathologic tissue examinationreveals demyelination with relative axon sparing.2,4 Symptomsresolve both with and without therapy, with therapy typicallyconsisting of a short course of corticosteroids.2,5
The vast majority of case reports describing MIL are associatedwith 5-FU and levamisole in combination.3 However, a singlecase occurred after administration of levamisole alone,5 andanother patient improved after discontinuation of levamisoledespite continuation of 5-FU.4 One other report describes multifocalleukoencephalopathy resulting from paclitaxel in two patientswho had received 5-FU without levamisole 4 and 11 weeks previously.Paclitaxel frequently produces peripheral and autonomic neuropathiesbut rarely produces transient encephalopathy and seizures.6Although no direct relationship has been demonstrated, discussionhas focused on levamisole as the most likely causative agent.
Our patient developed MIL resulting from 5-FU administrationnot in conjunction with levamisole. She received 5-FU in combinationwith carboplatin, which has not been reported to cause CNS toxicity.Symptoms in our patient developed 4 to 5 weeks after initiationof chemotherapy and were similar, although less severe, thanmost prior reports of MIL. Our patient experienced more commonside effects from 5-FU including mucositis and myelosuppression,which may also be secondary to systemic 5-FU toxicity, althoughmyelosuppression may also be seen with carboplatin. She didnot receive further 5-FU, and her symptoms resolved spontaneouslywithout treatment.
5-FU’s role as a causal factor is supported by the presenceof partial DPD deficiency, which has not been evaluated in patientswith MIL. DPD deficiency is known to place patients at increasedrisk for severe adverse reactions from 5-FU therapy.7 DPD isresponsible for more than 85% of pyrimidine catabolism, andpatients with DPD deficiency may demonstrate increased uraciland thymidine levels in serum and urine.8 DPD deficiency isnow estimated to occur in 3% of the adult cancer populationand consists of both complete and partial deficiency. Althoughinheritance is complex, results of familial studies demonstratean autosomal recessive pattern. Even in complete deficiencystates, affected individuals may be asymptomatic prior to pyrimidineadministration.9
Patients have a partial deficiency if the level of DPD activityfalls below the 95th percentile and a complete deficiency ifthe level is below the 99th percentile or is undetectable. Deficiencycan also be measured indirectly by measuring serum and urinarylevels of uracil. Results of previous studies have shown thatelevated uracil levels may be seen in complete deficiency butmay be normal in partial deficiency states.8
Neurologic toxicity is a well known, although uncommon, complicationof 5-FU and includes pancerebellar dysfunction, peripheral neuropathy,and encephalopathy. Encephalopathy after 5-FU occurs less frequentlyand is less clearly defined, with clinical features more typicalof a diffuse metabolic encephalopathy. It often occurs in thesetting of concomitant metabolic abnormalities, and cranialimaging may be normal.9 MIL appears to represent a distinctclinical and radiographic syndrome resulting from 5-FU administration,and it may be that patients with DPD deficiency are at increasedrisk for this life-threatening complication. The toxic effectsare likely caused by 5-FU itself rather than one of its derivativesbecause DPD deficiency results in a failure of 5-FU catabolism.10Drug interactions with levamisole and possibly other chemotherapeuticagents may play an important yet undefined role in the pathogenesisof this syndrome.
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Received May 15, 2000.
Accepted in final form August 25, 2000.
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