A 56‐year‐old woman with blindness and mental status changes

CLINICAL HISTORY

The patient is a 56‐year‐old woman with history of poorly differentiated squamous cell carcinoma of the esophagus, treated with neoadjuvant chemoradiation and esophagectomy. Approximately 3 years later, she presented with pancytopenia and was diagnosed with therapy‐related myelodysplasia, consistent with refractory anemia with excess blasts‐1. She was treated with induction (daunorubicin, cytarabine and cladribine) and consolidation (daunorubicin and cytarabine) chemotherapy. She then received reduced intensity conditioning (fludarabine, cyclophosphamide and total body irradiation) prior to undergoing double umbilical cord stem cell transplant. On day 35 post‐transplant, she developed progressive bilateral loss of vision.

A thorough ophthalmologic work‐up pinpointed no specific etiology; retinogram was normal while visual evoked potentials demonstrated severe bilateral conduction impairment. Brain MRI demonstrated mild to moderate FLAIR hyperintensities in the cerebral white matter, consistent with small vessel ischemic disease or treatment related changes. She then developed bilateral sensory loss in her lower extremities and was treated with plasmapharesis and corticosteroids, without improvement. She subsequently became encephalopathic, her pulmonary function deteriorated and her family declined further intervention. Permission for a full autopsy was given.

PATHOLOGY

On gross examination, the brain demonstrated prominent white matter pathology predominantly involving the left parietal lobe (Figure 1A). Microscopic examination of this area demonstrated a relatively demarcated area of vacuolization (Figure 1B) and myelin loss (LFB‐PAS, Figure 1C). Several small parenchymal lesions were also identified in the thalamus. Higher power images of the parietal lesion (Figure 1D) showed frequent axonal spheroids, further highlighted by neurofilament (Figure 1E) and APP immunostains. Numerous macrophages were present (CD68, Figure 1F) along with a moderate number of reactive astrocytes (GFAP, Figure 1G). In situ hybridization for JC virus was negative. What is the most likely diagnosis?

Figure 1.

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 1980s identified significant dose dependent neurotoxicity. At doses exceeding 100 mg/m², severe neurotoxicity occurred in 25–40% of patients 1, 4, 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, 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. 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.