Capecitabine-induced multifocal leukoencephalopathy: A report of five cases

5-Fluorouracil (5-FU) is primarily used in the treatment of breast and colon cancers. The most common neurologic toxicity is a cerebellar syndrome, but rare cases of encephalopathy are reported.¹ Capecitabine, an oral prodrug converted to 5-FU, is used in advanced breast and gastrointestinal malignancies.² A case of capecitabine-induced encephalopathy was recently reported.³ We report five additional cases of patients started on capecitabine for tumor progression who developed neurologic symptoms shortly thereafter and comment on the differences between capecitabine and 5-FU-induced encephalopathy.

Case reports.

Four patients with advanced breast and one with pancreatic carcinoma were started on capecitabine, 2 g/m²/day for tumor progression. All patients were women between 40 and 74 years of age. Within 7 days (range 3 to 7 days), all patients developed neurologic symptoms that prompted neurologic evaluation (table). Symptoms included nausea, confusion, short-term memory loss, headaches, vertigo, ataxia, dysarthria, and body shaking/stiffening. Brain MRI was performed in four patients and revealed increased signal on diffusion-weighted, fluid-attenuated inversion recovery and T2 sequences in the areas of the corpus callosum, brachium pontis, and deep periventricular matter. The splenium of the corpus callosum was primarily affected in all cases (figure). No pathologic enhancement occurred after gadolinium administration. Capecitabine was discontinued at the time of evaluation, and all patients improved over a few days with no or minimal neurologic deficits on discharge. Review of concomitant medications did not reveal any drugs with possible effects on the CNS before or at the time capecitabine was initiated. Four of our five patients had liver metastases without hepatic dysfunction. Two patients had brain metastases treated with whole-brain radiation or radiosurgery months earlier and were improved or stable when they presented.

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Figure. Case 1. (A and B) MRI shows areas of restricted diffusion with corresponding ADC map hypointensity in the brachium pontis, splenium, and genu of the corpus callosum and in the posterior centrum semiovale. (C) MRI shows changes in the fluid-attenuated inversion recovery (FLAIR) sequence. (D) MRI done 4 weeks later shows resolution of changes FLAIR sequences.

Discussion.

Many chemotherapeutic agents have been associated with neurotoxicity.⁴ Diagnosis of chemotherapy-induced neurotoxicity is based on three factors: known toxicities of an individual drug, the temporal relationship between drug administration and neurologic complication, and exclusion of other possible causes.

The main neurotoxicity of 5-FU is a cerebellar syndrome,¹ but multifocal cerebral leukoencephalopathy has been reported in patients treated with the combination of 5-FU and levamisole chemotherapy.^5–8 Neurologic symptoms of 5-FU appear within 19 weeks of starting chemotherapy (median 9 weeks) and include memory loss, confusion, ataxia, dysarthria, diplopia, and paresthesias. Periventricular, predominantly supratentorial, enhancing lesions within the white matter are seen. Despite improvement after the therapy is discontinued, some patients have persistent neurologic deficits. Steroids have been used, but with unclear benefit. Discontinuation of the causative chemotherapy is the treatment of choice.

Capecitabine is an oral prodrug converted to 5-FU. We report an additional five cases of multifocal leukoencephalopathy that developed soon after the initiation of capecitabine. Capecitabine leukoencephalopathy differs from 5-FU leukoencephalopathy in two ways: earlier onset and nonenhancing MRI changes centralized within the white matter structures. Severe toxicity, such as bone marrow suppression and gastrointestinal mucositis, after treatment with capecitabine and 5-FU due to dihydropyrimidine dehydrogenase deficiency has been described.⁹ The patient in Case 4 was tested for dihydropyrimidine dehydrogenase deficiency, which was not present. She was restarted on capecitabine 6 months later and has had no recurrence of her neurologic symptoms.

Peripheral neuropathy has been reported in two patients on capecitabine, but in those cases, it was a presenting symptom.¹⁰ None of our patients presented with neuropathy, so we attributed their neuropathy to prior chemotherapy with agents known to cause neuropathy (see table).

Capecitabine monotherapy has been used in a substantial number of patients and will continue to be used. In patients presenting with neurologic symptoms shortly after initiating therapy, the possibility of capecitabine-induced leukoencephalopathy should be considered. MRI with diffusion-weighted imaging may show restricted diffusion, but changes should also be seen on FLAIR and T2 sequences, although they may be more subtle. The natural history of this complication is unknown, but discontinuation of the drug leads to neurologic improvement within a few days. The effect of continuing therapy after presenting with neurologic symptoms is unknown, as is the recurrence of symptoms if patients are retreated with capecitabine. As more cases are recognized, clinicians may want to assess for dihydropyrimidine dehydrogenase deficiency, documentation of liver metastases, and hepatic function to determine whether these correlate with this complication.