J Neurooncol (2010) 97:425–427 DOI 10.1007/s11060-009-0028-9
CASE REPORT
Methotrexate-induced myelopathy responsive to substitution of multiple folate metabolites R. Ackermann • A. Semmler • G. D. Maurer E. Hattingen • F. Fornoff • J. P. Steinbach • M. Linnebank
•
Received: 15 June 2009 / Accepted: 25 September 2009 / Published online: 11 October 2009 Ó Springer Science+Business Media, LLC. 2009
Abstract Methotrexate (MTX)-associated myelopathy is a rare but serious subacute complication of MTX-based chemotherapy. We report the case of a woman with breast cancer and meningeal carcinomatosis who developed severe progressive myelopathy after four cycles of intrathecal MTX administration. We substituted high doses of the key metabolites of the methyl-transfer pathway: S-adenosylmethionine (SAM), 200 mg three times daily i.v.; folinate, 20 mg four times daily i.v.; cyanocobalamin, 100 lg once daily i.v.; and methionine, 5 g daily p.o. The patient’s paraparesis improved rapidly thereafter, and magnetic resonance (MR) imaging showed resolution of the intramedullary lesions. Genetic analyses revealed homozygosity for the A allele of methylenetetrahydrofolate reductase (MTHFR) c.1298A[C (p.E429A), whereas other genetic variants of folate/methionine metabolism associated with MTX neurotoxicity were not present. Substitution with R. Ackermann (&) G. D. Maurer J. P. Steinbach Dr. Senckenberg Institute of Neurooncology, Johann WolfgangGoethe University Frankfurt, Schleusenweg 2-16, 60528 Frankfurt, Germany e-mail:
[email protected];
[email protected] A. Semmler Department of Neurology, University Hospital, Bonn, Germany E. Hattingen Department of Neuroradiology, University Hospital, Frankfurt, Germany F. Fornoff Department of Gynaecology, University Hospital, Frankfurt, Germany M. Linnebank Department of Neurology, University Hospital, Zurich, Switzerland
multiple folate metabolites may be a promising strategy for the treatment of MTX-induced neurotoxicity. Keywords
Methotrexate Myelopathy Treatment
Case report A 54-year-old woman with leptomeningeal metastasis from breast cancer was admitted to our hospital with progressive paraparesis. Three months earlier, ventriculoperitoneal shunting for malresorptive hydrocephalus had been performed, followed by whole-brain radiation with 10 9 3 Gy. Because of recurrent leptomeningeal metastasis, four cycles of intrathecal chemotherapy with 15 mg MTX and 4 mg dexamethasone every 5 days were administered by lumbar puncture without folinate rescue. Five days after the last cycle, she developed bloody diarrhea, emesis, urinary retention, and pancytopenia. Filgrastim, platelet transfusions, and prophylactic antibiotics were initiated. There were no febrile episodes or infectious complications throughout the neutropenia. While the patient recovered from hematological and gastrointestinal toxicity, progressive neurological deficits emerged, and the patient was transferred to the neurooncology service. Upon admission, 16 days after the last intrathecal injection, a high-grade spastic paraparesis (Medical Research Council (MRC) grade 1–2) with urinary retention and anal incontinence was present. Sensory deficits were absent. No malignant cells were found in the cerebrospinal fluid (CSF). Protein was 2,828 mg/l (normal 0–550 mg/l) and lactate was 4.2 mmol/l (normal 1.2–2.1 mmol/l). The concentration of MTX in the CSF was below the limit of detection. Cultures from blood and CSF remained sterile. Magnetic resonance (MR) imaging of the spinal cord demonstrated hyperintense
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Fig. 1 a MRI of the cervical and thoracic spinal cord at presentation and b after 4 weeks of substitution with multiple folate metabolites. T2-weighted sagittal and transversal images at the level of the cervical spinal cord without administration of gadolinium. Diffusionweighted imaging (DWI) and apparent diffusion coefficient (ADC) pictures were not acquired
intramedullary lesions throughout the cervical and thoracic segments suggestive of subacute MTX-induced myelopathy (Fig. 1), without contrast enhancement. We substituted high doses of the key metabolites of the methyl-transfer pathway: S-adenosylmethionine, 200 mg three times daily i.v.; folinate, 20 mg four times daily i.v.; cyanocobalamin, 100 lg once daily i.v.; and methionine, 5 g daily p.o. Three days later, marked improvement with resolution of paraparesis from MRC grade 1–2 to MRC grade 3 was noted. After 1 week, all therapy was continued orally. There was some further improvement, and the patient was referred to a rehabilitative program. Upon reevaluation 1 month later, there was residual paraparesis (MRC 3–4) and persisting urinary incontinence. MR imaging showed resolution of the intramedullary lesions (Fig. 1). Genetic analyses revealed homozygosity for the A allele of methylenetetrahydrofolate reductase (MTHFR) c.1298A[C (p.E429A), whereas other genetic variants of folate/methionine metabolism associated with MTX neurotoxicity were not present (data not shown) [1].
Discussion Acute and chronic encephalopathies are the most common types of MTX-induced neurotoxicity. In contrast, subacute
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myelopathy is rare [2]. While it is notable that folinate rescue was not administered in our patient, this is often viewed as dispensable for low-dose MTX regimens including intrathecal therapy. There is uncertainty regarding the value and safety of intrathecal therapy with MTX in patients with implanted ventricular-peritoneal shunt systems. MTX may, on the one hand, clear from the CSF too rapidly. On the other hand, shunt-induced alterations of CSF circulation may possibly also induce prolonged retention of MTX in the spinal compartment if drainage of the spinal compartment is impaired. In retrospect, intrathecal therapy induced a remission in this patient, who had progressed after radiotherapy. Our patient was heavily pretreated with several chemotherapeutics (epirubicin, docetaxel, capecitabine), but her bone marrow function normalized rapidly thereafter. Therefore, cumulative bone marrow suppression after application of MTX in this dosage appears unlikely. Additionally, altered CSF circulation may have also enhanced neurotoxicity, e.g., by prolonged retention of MTX in the spinal compartment, but this remains speculative [3]. The severe MTX-induced toxicity in our patient—both systemic and in the CNS—is therefore indicative of hypersensitivity towards MTX. Systemic and intrathecal therapy with MTX interferes with folate/methionine metabolism, increasing both plasma and CSF concentrations of homocysteine and decreasing SAM, methionine, and 5-methyltetrahydrofolate concentrations [4]. MTX neurotoxicity is associated with polymorphic mutations of folate/methionine metabolism that may influence nucleic acid and SAM synthesis as well as homocysteine metabolism. MTHFR is necessary to synthesize a cofactor for methionine synthesis, 5-methyltetrahydrofolate, from 5,10-methylenetetrahydrofolate. Homozygosity for the wild-type A allele of the MTHFR variant c.1298A[C, as observed here, is common in the normal Caucasian population, and is associated with slightly increased enzymatic activity [5, 6]. This variant was recently discovered as a risk factor for the appearance of asymptomatic cerebral white-matter changes under MTX therapy, although it is not known as a risk factor for neurotoxicity after systemic ‘‘low-dose’’ MTX therapy. However, no published reports concerning the impact of A allele homozygosity on neurotoxicity after intrathecal therapy are available [1]. Other yet undiscovered mechanisms may also influence MTX sensitivity. Nevertheless, substitution with SAM, 5-methyltetrahydrofolate or methionine normalizes CSF levels of folate/ methionine metabolites and promotes remyelination in children affected by inborn errors of folate/methionine metabolism [7]. To achieve the best functional MTX rescue in the affected neural tissue we thought it a promising strategy to substitute SAM directly and stabilize the endogenous production of SAM by substituting different
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folate metabolites. The optimal doses of these drugs are not known. We employed the doses that have been found safe in the treatment of other disorders. SAM, the universal methyl donor, systemic, and the sole one in the central nervous system is known to cross the blood–brain barrier easily [8, 9]. Folate and vitamin B12 are actively transported into the CSF [10, 11]. Methionine uses facilitative transport to cross the blood–brain barrier [12]. Regarding the necessity for folate metabolite replacement, time course and outcome of this case somewhat resemble delayed leukoencephalopathy with stroke-like presentation (DLEPS) observed with a variety of chemotherapeutic agents [13]. DLEPS typically is a benign and self-limited condition that resolves in the majority of cases when exposure to the noxious agent is interrupted. However, the syndrome observed in our patient was markedly distinct from the DLEPS spectrum. First, toxicity concerned the spinal cord with rapidly progressive neurological deficits until therapy. Further, the majority of the published cases of MTX-induced myelopathy reported had a severe and often fatal course, although some remissions were observed. Therefore, we feel that this experimental treatment was justified. To our knowledge, this is the first report of substitution of multiple metabolites of folate/methionine metabolism for subacute MTX-induced neurotoxicity. The patient’s rapid improvement following initiation of therapy may indicate a benefit derived from this regimen given the relentless progression of symptoms before, although spontaneous recovery from MTX-induced myelopathy cannot fully be excluded as an alternative explanation. In summary, substitution with SAM itself accompanied by components necessary for endogenous SAM synthesis, such as methionine, folate/folinate, and vitamin B12, may be a safe and promising strategy for treatment of MTX-induced neurotoxicity. Acknowledgement The Dr. Senckenberg Institute of Neurooncology and the Hertie Chair for Neurooncology are supported by the charitable foundations Dr. Senckenberg Foundation and Hertie Foundation.
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