Myelopathy mimicking subacute combined degeneration in a Down syndrome patient with methotrexate treatment for B lymphoblastic leukemia: Report of an autopsy case

We report clinicopathological features of a 23‐year‐old woman with Down syndrome (DS) presenting with subacute myelopathy treated with chemotherapy, including intravenous and intrathecal administration of methotrexate (MTX), and with allogenic bone‐marrow transplantation for B lymphoblastic leukemia. Autopsy revealed severe demyelinating vacuolar myelopathy in the posterior and lateral columns of the spinal cord, associated with macrophage infiltration, marked axonal loss and some swollen axons. Pathological changes of posterior and lateral columns were observed from the medulla oblongata to lumbar cord. Proximal anterior and posterior roots were preserved. Cerebral white matter was relatively well preserved. There were no vascular lesions or meningeal dissemination of leukemia. Longitudinal extension of cord lesions was extensive, unlike typical cases of subacute combined degeneration (SACD), but distribution of lesions and histological findings were similar to that of SACD. DS patients show heightened sensitivity to MTX because of their genetic background. Risk factors for toxic myelopathy of DS are discussed, including delayed clearance of MTX despite normal renal function, alterations in MTX polyglutamation and enhanced folic acid depletion due to gene dosage effects of chromosome 21. Alteration of folate metabolism and/or vitamin B₁₂ levels through intravenous or intrathecal administration of MTX might exist, although vitamin B₁₂ and other essential nutrients were managed using intravenous hyperalimentation. To the best of our knowledge, this is the first report of an autopsy case that shows myelopathy mimicking SACD in a DS patient accompanied by B lymphoblastic leukemia. The case suggests a pathophysiological mechanism of MTX‐related myelopathy in DS patients with B lymphoblastic leukemia mimicking SACD.