Brain Pathology Case of the Month - April 2008


Diagnosis: Methotrexate-induced leukoencephalopathy

Discussion: Acute and delayed chemotherapy-induced white matter abnormalities occur in a variety of clinical settings including treatment for lymphoma, leukemia, glioma and metastatic disease as well as prophylactic treatment for acute lymphoblastic leukemia and Burkitt lymphoma (2) The spectrum of pathological changes almost always includes myelin loss with some degree of axonopathy but also encompasses a spectrum of additional abnormalities ranging from mild gliosis with macrophages to vascular abnormalities and coagulative necrosis. Pathologic changes described in patients with hyperacute and acute leukoencephalopathy, which may be better termed acute disseminated leukoencephalopathy (ADL), differ from those described for classic disseminated necrotizing leukoencephalopathy (DNL), since necrosis may be lacking. The underlying pathogenic mechanism for acute chemotherapy induced leukoencephalopathy is likely different from that of delayed DNL, and the MR imaging findings differ as well, showing severe restricted diffusion abnormalities but a lack of contrast enhancement (3, 7, 8, 4).

Acute disseminated leukoencephalopathy (ADL) is proposed as a broad clinical-radiological term describing a range of abnormalities from mild reversible clinical symptoms with MRI changes to profound encephalopathy resulting in death. We suspect that the underlying pathology in many of these cases correlates with what has been described as chemotherapy induced toxic leukoencephalopathy, which is a specific pattern seen in patients who die in the hyperacute to subacute phase of this process (5). The histologic features described for hyperacute to subacute toxic leukoencephalopathy are similar among cases although the distribution of lesions is variable. The key histopathologic features in our case are similar to those of previously reported cases and include myelin pallor, axonopathy, macrophage infiltration and vacuolation of neuropil. These findings are analogous to those described in an animal model of acute methotrexate intoxication (9). We believe that demyelination and axonopathy in this case reflect a hyperacute, toxic or idiosyncratic response to chemotherapy with a pathogenesis that is distinct from that of delayed DNL. The key histopathological distinction between chemotherapy induced toxic leukoencephalopathy and DNL is the lack of both coagulative necrosis and vasculopathy, preservation of oligodendroglial cells and prevalence of macrophages.

MRI studies have suggested that contrast enhancement correlates with vascular abnormalities and necrosis in cases of DNL (6). However, little is known about the imaging characteristics of a hyperacute or potentially reversible phase of leukoencephalopathy. There is scant literature on acute diffusion abnormalities associated with chemotherapy, but recent reports suggest there is a reversible component to the deep white matter abnormalities in the setting of chemotherapy, such as methotrexate or 5-flourouracil (3, 8, 7, 10). This reversibility of restricted diffusion in this case is in distinct contrast to that seen with acute stroke. Since diffusion weighted imaging reflects the in vivo process of water diffusion between and within cells and the interstitium, it is sensitive to detecting hyperacute and acute injury. In particular, reversible diffusion weighted abnormalities associated with acute methotrexate-induced leukoencephalopathy have been described (3, 8, 7), however these have not included pathologic correlation. (6, 4). Symptoms appear to lessen as diffusion abnormalities resolve (usually over 1-3 weeks), if there is no significant contrast enhancement or are only mild T2-hyperintense abnormalities in the acute phase (3, 8, 7). It seems in the aforementioned literature these findings usually reverse on DWI, although T2 abnormalities may or may not develop/persist as a chronic result. A study by Rollins et al. of five patients suggested that these diffusion abnormalities and symptoms may not recur on repeat administration of methotrexate (7). Hence, this case likely represents the most severe end of the spectrum in the acute phase. It illustrates the rapid onset and worsening over a three day period; and that even if the offending agent is removed, the insult may be too severe to reverse. The case described here appears to differ dramatically from those of DNL, in which severe T2 prolongation and usually contrast enhancing lesions occur in the white matter, consistent with blood-brain barrier injury (1, 6).

This case demonstrates the inherent difficulties associated with determining whether chemotherapy induced diffusion weighted white matter abnormalities are reversible or irreversible. Neuropathological findings in this case support the interpretation that restricted diffusion resulted from cytotoxic edema as evidenced by enlargement of oligodendroglial cells, axonal swellings and enlarged spaces within or between myelin sheaths surrounding neuronal processes. In diffusion-positive reversible cases of acute leukoencephalopathy, imaging abnormalities often resolve, according to the sparse literature described. This suggests that although axonal abnormalities may be permanent, significant remyelination may occur as toxicity and edema resolve. The term ADL (acute disseminated leukoencephalopathy) may be more appropriate than DNL in the acute phase of chemotherapy induced toxic leukoencephalopathy. This term may also be more appropriate in the acute phase since similar MRI diffusion abnormalities can occur diffusely and symmetrically from other insults totally unrelated to chemotherapy such as carbon monoxide toxicity and hypoxic-ischemic encephalopathy.


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  10. Tha KK, Terae S, Sugiura M, Nishioka T, Oka M, Kudoh K, et al. (2002) Diffusion-weighted magnetic resonance imaging in early stage of 5-fluorouracil-induced leukoencephalopathy. Acta Neurol Scand 106: 379-86.

Contributed by Karen SantaCruz MD, Alex McKinney MD, Stephen Kieffer MD, John Tulloch MD

International Society of Neuropathology