Presentations

Abstract

Introduction:

Methotrexate (MTX) is a common anti-folate analog that is used in chemotherapy and autoimmune conditions. Due to MTX inhibition of DNA replication, it is an important chemotherapeutic agent. Intrathecal administration of MTX has been associated with an increased risk of neurotoxicity with symptoms of focal neurological deficits (FNDs), confusion, disorientation, and even seizures. MTX-induced Leukoencephalopathy (LE) can be acute and reversible or lead to irreversible chronic long-term FNDs due severe extensive neural damage. It is important to consider systematic medical imaging (magnetic resonance imaging, MRI) before and after MTX treatment to monitor for MTX-related acute neurotoxicity. We discuss the case of a 60-year-old female with acute lymphoid blast crisis of chronic myeloid leukemia who developed neurological symptoms 9 days post intrathecal MTX administration.

Case Information:

A 60-year-old female with a past medical history of chronic myeloid leukemia (CML) presenting with acute lymphoid blast crisis of CML under treatment with dasatinib. The patient was hospitalized and received intrathecal MTX infusion without immediate complications and underwent a second dose of intrathecal MTX with dexamethasone the following day. Nine days after, the patient had an episode of headaches (8/ 10), which failed to subside with over-the-counter analgesics. The headaches were associated with intermittent episodes of arterial hypertension, non-fluent speech, and bradypsychia. The patient was afebrile during these episodes.

On physical examination, the patient was awake, oriented, with isochoric and reactive pupils, no diplopia, and with conserved overall cranial nerve function. Language was preserved with no motor or sensory deficits. Coordination was preserved and no meningeal signs.

A head computed tomography and cerebral spinal fluid (CSF) sample from a lumbar puncture were normal. The initial differential diagnosis was posterior reversible encephalopathy syndrome (PRES). An MRI with gadolinium revealed confluent enhancing fluid- attenuated inversion recovery hyperintensity in the frontal, left parieto-occipital regions, and semioval centers. There was no evidence of restricted diffusion, midline shift or mass effect. The transient LE findings lead to progressive multifocal leukoencephalopathy (PML) as a probable diagnosis. Repeat CSF analysis was normal and JC virus PCR was negative. MTX-induced LE was the final diagnosis and MTX therapy was suspended. A follow-up MRI of the brain showed a decrease in hyperintense lesions.

Discussion: / Clinical Findings:At lower doses, MTX inhibits the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, leading to a decrease in Adenosine and Guanine breakdown, adenosine-induced vasodilation, and subacute, chronic toxicity due to increasing cerebrospinal fluid levels of homocysteine. Homocysteine is metabolized into homocysteine acid and cysteine sulfonic acid which causes seizures and excitotoxic neuronal cell death, causing direct toxicity to the vascular endothelium. Developing MTX-mediated leukoencephalopathy is dose-dependent, with high doses of IV MTX associated with the development of acute LE in 3-15% of cases with a recurrence rate of 10- 56% if therapy is continued. Intrathecal administration of MTX is associated with the highest risk of acute LE versus high-dose IV administration.

MTX-induced LE on neuroimaging shows hyperintensity signals in areas consistently vulnerable to hypoxic/ischemic degeneration and damage due to excitotoxic action of N-methyl aspartate (NMA). This is partly due to the elevated number of NMDA receptors seen in these areas, rendering these neuronal cell populations sensitive to excitotoxicity.

Conclusion:

Currently, there is no widely established protocol in place to ensure that patients receiving MTX are monitored through MRI. Imaging is usually ordered in response to new neurologic symptoms, however, continued monitoring starting at the time of treatment is imperative to prevent irreversible neurologic deficits in patients who may present asymptomatic, or with nonspecific symptoms.