021 Fludarabine-induced subacute, often fatal leukoencephalopathy: a case series

Fludarabine, a purine agonist, is associated with a rare dose-dependent risk of severe and often fatal neurotoxicity. Referencing the clinical course of seven such patients, we report the clinical, radiological, and pathological findings in one patient who developed a fatal leukoencephalopathy to highlight potential mechanisms of fludarabine-induced neurotoxicity. Of the seven cases, one presented with paraparesis, two with cognitive impairment, and four with blurred vision; five cases were fatal, with a variable time course of symptom onset and progression. All patients had unexplained progressive, symmetric leukoencephalopathy on serial brain MRIs. One patient underwent post-mortem neuropathological examination; she was a 49-year-old female with severe aplastic anaemia and myelodysplastic syndrome who had received fludarabine at 25 mg/m2 for five days prior to stem cell transplantation. Thirteen days later, she developed rapidly-progressive cognitive deterioration and motor weakness. Serial brain MRIs showed extensive leukoencephalopathy extending into the midbrain and pons bilaterally. She passed away at day 39 post-transplant. Histopathology revealed diffuse, gross softening of the white matter and microscopic evidence of a demyelinating process with diffuse myelin loss, axonal injury, and spheroid formation. Electron microscopy revealed abnormally proliferative, reticulated, densely packed endoplasmic reticulum, suggesting a toxic, progressive demyelinating process.