Contributed by Karen SantaCruz MD1, Alex McKinney MD2, Stephen Kieffer MD2, John Tulloch MD3
1Department of Laboratory Medicine and Pathology, 2Department of Radiology and 3Department of Neurology, University of Minnesota
The patient was a 50-year-old man who presented with six months of abdominal pain, a 15-20 pound weight loss, night sweats and chills. Biopsies of the stomach revealed Burkitt lymphoma with retroperitoneal involvement. A staging bone marrow biopsy was negative for tumor. However, tumor burden was large and chemotherapy was elected. Cyclophosphamide and prednisone were given prior to the start of a chemotherapy regimen consisting of ifosfamide, mesna, methotrexate, leucovorin, vincristine, Ara-C, etoposide and Decadron. Intrathecal methotrexate was given twice. The patient developed fevers shortly before completion of this protocol. Pan-cultures remained negative. The patient tolerated chemotherapy until the final day (7 days after the last intrathecal dose of methotrexate) when he became confused. Over the following day this evolved into an agitated delirium. Neurologic exam later that day showed decerebrate posturing in an intubated, comatose patient with intact brainstem function. Head CT showed no evidence of hemorrhage and MRI showed minimal findings on diffusion and FLAIR images. EEG showed changes suggestive of drug effect but no significant focal abnormalities. CSF showed normal glucose and protein levels and no white blood cells. Clinically, the patient failed to improve over the next three days. MRI imaging studies were repeated and showed severe changes. The patient expired 12 days after symptom onset.
The patient presented for MRI with acute mental status changes 7 days after receiving intrathecal methotrexate for Burkitt lymphoma. Only minimal findings were present on diffusion and FLAIR images. Diffusion weighted imaging demonstrated minimal abnormality in the right forceps major and deep parietal white matter (Fig. 1), without significant abnormality on the FLAIR images, and without cortical involvement (Fig. 2). These were interpreted as artifactual or minimal chronic white matter changes. The patient's symptoms worsened, and the patient returned for MRI three days later. The second MRI scan demonstrated diffuse and relatively symmetric diffusion abnormalities in the deep and periventricular white matter and to a lesser degree within the corpus callosum splenium, with the Apparent Diffusion Coefficient (ADC) in the centrum semiovale (0.28 x 10-3 mm2/second bilateral centrum semiovale) decreased relative to the initial scan (0.63 x 10-3 mm2/sec.) and to the thalami (0.86 x 10-3 mm2/sec., same scan) (Fig. 3) and (Fig. 4). This was confirmed on the ADC maps (Fig. 5) with only minimal abnormal signal on the FLAIR images (Fig. 6); hence not representing "T2 shine-through." There was no significant abnormal contrast enhancement. The findings of restricted diffusion were interpreted as likely related to cytotoxic edema within the white matter or intramyelinic edema, thought to be secondary to chemotherapy. The chemotherapy was withdrawn, but the patient expired 9 days later.
At autopsy the formalin fixed white matter showed subtle gray discoloration in parieto-occipital subcortical regions. The gyral pattern was symmetrical without cerebral edema.
Histopathologic examination revealed a range of pathologic abnormalities in essentially all sections of subcortical white matter examined. Most sections showed sparing of subcortical U-fibers. Deep white matter and brainstem tracts were uninvolved. The most pervasive abnormality was of white matter pallor with vacuolation of the neuropil. Certain histologic features suggested that these vacuoles were predominantly within cellular processes rather than interstitial, however enlargement of pericellular spaces was also noted. Occasional swollen oligodendroglial cells with lightly eosinophilic cytoplasm were noted (Fig. 7). Luxol fast blue staining suggested the possibility of enlarged spaces within or between myelin sheaths and axons and modified Bielschowsky silver staining revealed axonal swellings (Figs. 8, 9). Axonal spheroids were common in hematoxylin and eosin stained sections and immunohistochemical staining with amyloid precursor protein highlighted these (Fig. 10). Macrophage infiltration was prominent in severely affected regions and reactive astrocytes appeared to envelop edematous spaces (Figs. 11, 12).