SUMMARY: Subacute MTX-induced encephalopathy is characterized by an abrupt onset of focal neurologic deficits within days after intrathecal or systemic therapy. Demyelination is one proposed mechanism. We describe the neuroimaging features of 2 patients with clinical symptoms of subacute encephalopathy after intrathecal and systemic MTX therapy. DWI showed restricted diffusion, indicating cytotoxic edema. MTI yielded no evidence of demyelination in either patient because there was no loss of MTR in areas of restricted diffusion.ABBREVIATIONS: ADC ϭ apparent diffusion coefficient; ALL ϭ acute lymphoblastic leukemia; DWI ϭ diffusion-weighted imaging; IT ϭ intrathecal; IV ϭ intravenous; MTI ϭ magnetization transfer imaging; MTR ϭ magnetization transfer ratio; MTX ϭ methotrexate I n the prophylaxis of central nervous system leukemia, IT MTX has largely replaced cranial irradiation and has lead to improved survival outcomes.1 Toxic effects of MTX include mucositis, myelosuppression, nephrotoxicity, hepatotoxicity, and neurotoxicity with acute (within hours), subacute (days to weeks after administration), and chronic (after months and years) encephalopathy.
2Subacute MTX-induced encephalopathy is characterized by a delayed onset of strokelike symptoms, such as aphasia, hemiparesis, and ataxia. Complete resolution of symptoms after therapy is usually seen in patients with encephalopathy. The pathophysiology of MTX-induced encephalopathy is incompletely understood. Demyelination and adenosine release have been proposed to contribute to the development of the disease. [3][4][5] DWI has been used to diagnose cytotoxic edema in subacute MTX-induced encephalopathy 6 but does not assess demyelination. MTI is a diagnostic tool known to be sensitive to demyelination. 7 We report on 2 cases of subacute MTX-induced encephalopathy following IT MTX therapy in pediatric patients with ALL, who presented with typical neuroimaging without signs of demyelination on MTI.
Case ReportsPatient 1, a 13-year-old girl with biphenotypic ALL, received chemotherapy according to the COALL-07-03 protocol (high-risk standard).8 Twelve days after the third treatment with 12 mg of IT MTX, she developed prickling sensations and a central facial nerve paresis on the right side. Conventional MR imaging showed changes on T2-weighted imaging with faint hyperintensity of the white matter in both hemispheres. DWI hyperintensity and low ADC were observed in the centrum semiovale of both hemispheres, corresponding to restricted diffusion.MTI used two 2D gradient-echo sequences. The first acquisition had no saturation pulse. The second used a saturation pulse 1.2 kHz below H 2 O frequency. The MTR is the percentage of signal-intensity loss induced: MTR ϭ (S 0 Ϫ S s ) / S 0 ϫ 100%, where S 0 is the signal intensity of a pixel obtained from the sequence without the saturation pulse and S S is the signal intensity with the saturation pulse.MTR maps showed symmetric values of the white matter, and there was no loss of MTR in areas of DWI or T2 hyperintensity (Fig ...