A 49 year old man with HIV (on HAART therapy), end-stage renal disease, and anal cancer presented with altered mental status, having just begun chemotherapy with mitomycin and a continuous infusion of 5-fluorouracil. Exam was significant for lethargy, difficulty concentrating, and confusion as well as occasional lip-smacking. Routine laboratory analysis was normal, other than elevated BUN and creatinine. Workup for toxic, metabolic, and infectious causes of acute encephalopathy was normal, including a normal ammonia level. Computed tomography of the head revealed no acute process. The patient’s continuous 5-FU infusion was stopped, and he underwent hemodialysis without improvement in mental status.
Electroencephalogram showed diffuse encephalopathy without epileptiform activity. Diffusion-weighted images on MRI with identified an area of restricted diffusion in the splenium of the corpus callosum. Cerebrospinal fluid analysis was normal along with negative gram stain, culture, India Ink, Cryptococcal antigen, and VDRL. Four days after his 5-FU infusion was withheld, his mental status began to improve.
Discussion:
This case exhibits a rare complication of a common chemotherapeutic agent, 5-FU. The mechanism for the neurotoxic effect of 5-FU is unknown, although cases in the literature have postulated myelin swelling, vacuolization, and destruction. Direct toxicity to CNS progenitor cells and oligodendrocytes has been suggested as well. This correlates well to the MRI findings typically seen in 5-FU encephalopathy, which in our case showed an area of restricted diffusion in the corpus callosum, the largest white matter structure in the brain.
An interesting point is the involvement of ammonia, a catabolic byproduct of 5-FU, in the pathogenesis of encephalopathy. Ammonia level was normal in our patient, but hyperammonemia is a common finding in many cases in the literature. Development of encephalopathy in our patient suggests that ammonia may not play a singular role in the neurotoxic effect of the drug. This rather suggests direct neurotoxic effects from 5-FU or a buildup of metabolites, such as fluoroacetate, playing a more significant role. Presence of end-stage renal disease and use of a continuous infusion of 5-FU may have contributed to toxicity as well.
Conclusions:
The mechanism of 5-FU encephalopathy leading to reversible white matter damage is not entirely clear. Therefore, diffusion-weighted MRI is an important tool in the workup for a patient on 5-FU presenting with acute encephalopathy. While there is still more to learn about the neurotoxic effects of 5-FU, it is encouraging that limited evidence suggests that prompt diagnosis and withdrawal of the drug is associated with reversible and favorable clinical outcomes.