Final Diagnosis -- Leukoencephalopathy

FINAL DIAGNOSIS

Leukoencephalopathy, consistent with fludarabine neurotoxicity.

DISCUSSION

Leukoencephalopathy is a well-known complication of cancer chemotherapy, including methotrexate, BCNU, melphalan, cytarabine, 5-fluorouracil, levamisole, cisplatin, and fludarabine (3). Fludarabine is a purine analog chemotherapy drug currently used in the treatment of chronic lymphocytic leukemia and for reduced intensity conditioning prior to hematopoietic stem cell transplant. The initial phase I/II trials of fludarabine in the 1980's identified significant dose dependent neurotoxicity. At doses exceeding 100 mg/m2, severe neurotoxicity occurred in 25-40% of patients (1, 6), but was rare (0.2%) at lower doses (1). The toxicity was delayed, occurring weeks to months after the completion of treatment. Patients presented with a relatively consistent set of symptoms, including vision loss, mental status changes, and myelopathic symptoms (5), which were largely irreversible and fatal.

Autopsy in these cases demonstrated variably severe white matter pathology, characterized by myelin loss, macrophage infiltration, vacuolation, and axonal damage (1, 2, 4). The pathology was typically most severe in the parietal and occipital lobes involving the optic tracts but was variably seen in the cerebellum, brainstem, and spinal cord dorsal columns.

The differential diagnosis in this case is broad, as leukoencephalopathy has numerous, diverse etiologies. Demyelinating disease is an important diagnostic consideration, with progressive multifocal leukoencephalopathy (PML) of particular concern. However, the extent of axonal damage in this case is unusual in a typical demyelinating lesion. Additionally, the lesion lacked the bizarre astrocytes and viral inclusions seen in PML and JC virus in situ hybridization was negative. In addition, as antineoplastic drugs are almost always used in combination and often with radiation, it may be difficult to clearly identify the causative agent.

In this case, although the patient had received radiation and multiple chemotherapy drugs, her clinical presentation, the timing of symptom onset, and autopsy findings were very characteristic fludarabine toxicity.

REFERENCES

1. Chun HG, Leyland-Jones BR, Caryk SM, Hoth DF (1986) Central nervous system toxicity of fludarabine phosphate. Cancer Treat Rep.70(10):1225-8.
2. Lee MS, McKinney AM, Brace JR, Santacruz K (2010) Clinical and imaging features of fludarabine neurotoxicity. J Neuroophthalmol.30(1):37-41.
3. Perry A, Schmidt RE (2006) Cancer therapy-associated CNS neuropathology: an update and review of the literature. Acta Neuropathol.111(3):197-212.
4. Spriggs DR, Stopa E, Mayer RJ, Schoene W, Kufe DW (1986) Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study. Cancer Res.46(11):5953-8.
5. Von Hoff DD (1990) Phase I clinical trials with fludarabine phosphate. Semin Oncol.17(5 Suppl 8):33-8.
6. Warrell RP, Jr., Berman E (1986) Phase I and II study of fludarabine phosphate in leukemia: therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol.4(1):74-9.

Contributed by Rachael A. Vaubel, MD, PhD and R. Ross Reichard, MD