Can 5-Fluorouracil (5-FU) cause confusion?

5-Fluorouracil (5-FU) and Confusion

Yes, 5-FU can cause confusion and other neurological symptoms as a recognized but uncommon adverse effect.

Neurological Side Effects of 5-FU

5-FU is known to cause several types of neurotoxicity, including:

1. Acute Confusion/Encephalopathy

   • Manifests as confusion, disorientation, drowsiness, and agitation 1
   • Can occur within days of administration (median onset 3 days) 1
   • Often accompanied by dysarthria in severe cases 2

2. Leukoencephalopathy

   • Characterized by white matter changes visible on MRI 1, 2
   • Can affect the corpus callosum, particularly the splenium 2
   • Usually reversible with drug discontinuation

3. Hyperammonemic Encephalopathy

   • Presents with confusion, disorientation, nausea, and vomiting 3
   • Associated with elevated ammonia levels
   • More common with infusional 5-FU than oral capecitabine 3

Risk Factors for 5-FU Neurotoxicity

The most significant risk factor is dihydropyrimidine dehydrogenase (DPD) enzyme deficiency:

• DPD is the primary enzyme responsible for 5-FU metabolism
• Deficiency leads to drug accumulation and toxicity 4
• Can cause severe neurological symptoms including acute confusion, seizures, and metabolic encephalopathy 4
• FDA label warns that patients should discontinue therapy if symptoms of DPD enzyme deficiency develop 5

Mechanism of Neurotoxicity

5-FU readily crosses the blood-brain barrier through passive diffusion despite its short half-life (<30 minutes) 6. It can:

• Induce apoptosis in neurogenic regions of the brain
• Depress cell proliferation in the hippocampus
• Reduce levels of doublecortin (marker for newly formed neurons)
• Decrease brain-derived neurotrophic factor (cell survival modulator) 6

Other Neurological Effects

Beyond confusion, 5-FU can cause:

• Memory impairment (part of "chemo brain" phenomenon) 6
• Executive function deficits
• Sensory gating issues
• Seizures in severe cases 4

Management of 5-FU-Induced Confusion

1. Immediate discontinuation of 5-FU therapy
2. Supportive care until symptoms resolve
3. Consider alternative agents if continued fluoropyrimidine therapy is necessary:
   • Capecitabine may be tolerated in some patients who experienced 5-FU-induced encephalopathy 3
   • Use lower doses with careful monitoring

Prognosis

The prognosis for 5-FU-induced neurotoxicity is generally good if recognized and treated promptly 2. Most patients experience complete neurological recovery with supportive management 1.

Clinical Pearls

• Confusion occurring within days of starting 5-FU therapy should raise suspicion for drug-induced neurotoxicity
• Consider DPD deficiency in patients with severe or unexpected reactions to standard doses
• MRI may show characteristic changes in the white matter, particularly in the corpus callosum
• Symptoms typically resolve with drug discontinuation and supportive care
• Patients with history of 5-FU neurotoxicity may tolerate capecitabine at reduced doses

While 5-FU is more commonly associated with other toxicities like diarrhea (occurring in up to 47% of patients with certain regimens) 7 and cardiotoxicity 7, clinicians should remain vigilant for neurological symptoms, particularly confusion, which can indicate a serious adverse reaction requiring prompt intervention.