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Neuroradiology Case of the Week

Case 402

April 2009

Ashwani K. Sharma, MD, Jeevak Almast, MD
and PL Westesson, MD, PhD, DDS

Clinical Presentation: A 20-year-old male, status post-treatment for AML, presented with acute confusion. The Ommaya reservoir is blocked.

Imaging Findings: Complications related to chemotherapy delivery via the Ommaya reservoir, periventricular white matter signal hyperintensity and/or focal signal abnormalities around the ventricular catheter.
     A unique and serious complication of methotrexate treatment is progressive leukoencephalopathy. This entity involves the diffuse white matter (including white matter U-fibers) and lesions can be both hemorrhagic or non-hemorrhagic. Focal brain necrosis due to extravasation of methotrexate secondary to obstruction of the tip of a ventricular Ommaya reservoir catheter has also been described.

Diagnosis: Focal brain necrosis due to extravasation of methotrexate through blocked Ommaya reservoir

Discussion: Intrathecal chemotherapy can lengthen survival and ameliorate symptoms in patients with widespread leptomeningeal metastases [1].
     Methotrexate (MTX) can influence the CNS through several metabolic pathways, and different possible explanations for the neurotoxicity of MTX have been proposed. Firstly, MTX is an antimetabolite that inhibits dihydrofolate reductase (DHFR) and thereby the formation of tetrahydrofolate. Subsequently, the synthesis of many types of macromolecules including myelin proteins and lipids that have a high turnover is impaired. Secondly, inhibition of DHFR also leads to deficiency of S-adenosylmethionine (SAM). SAM is known to be important in the maintenance of the myelin sheath and its deficiency is presumed to be a cause of the demyelination observed during treatment of children with MTX [2].
     The two primary means of delivering intrathecal chemotherapy are Ommaya reservoirs and repeat lumbar puncture. Ommaya reservoirs offer many advantages over repeat lumbar punctures, including greater patient comfort, diminished risk for patients with thrombocytopenia, more consistent drug levels, and possibly greater clinical efficacy [3,4,5]. Despite these advantages, there are potential complications associated with Ommaya reservoir placement and use. Intracranial hemorrhages, infection and catheter malposition requiring revision are some of the complications [5]. Neurological deficits and even death have been reported as a result of malpositioned catheters [6].
     Most complications are acute and occur in the immediate postoperative period, but treatment-related imaging abnormalities can be noted months to years after intrathecal or intraventricular chemotherapy administration [5,7]. Patients may be asymptomatic but have markedly abnormal imaging findings, especially periventricular signal abnormalities on CT and MRI scans [8].
     Acute MTX leukoencephalopathy has been well described clinically and MRI findings have been well documented. This leukoencephalopathy is most often asymptomatic, with only transient changes in deep cerebral white matter on MRI [2].
     In a prospective study of 33 children with ALL, serial MRI scans were performed during treatment (at least four times: at the beginning of treatment, after induction, after consolidation or during maintenance, and at the end of the treatment). MRI showed transient white-matter changes in three children (9%), located in the periventricular frontoparietal white matter, appeared after consolidation treatment and disappeared by the end of treatment [9].
     In another study, lesions not only involved deep white matter, but also supratentorial cortex and subcortical white matter, thalami and cerebellar cortex and white matter [2].
     Focal brain necrosis due to extravasation of methotrexate secondary to obstruction of the tip of a ventricular Ommaya reservoir catheter has also been described. This complication is very rare, and is noticed in only 0.6% of patients who had intraventricular MTX therapy. The cause of this syndrome is a displacement of the catheter into parenchyma [10,11].
     A unique and serious complication of methotrexate treatment is progressive leukoencephalopathy. This entity involves the diffuse white matter (including white matter U-fibers) and lesions can be both hemorrhagic and non-hemorrhagic.

References:

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2. Ziereisen F, Dan B, Azzi N, Ferster A, Damry N, Christophe C. Reversible acute methotrexate leukoencephalopathy: atypical brain MR imaging features. Pediatr Radiol. 2006 Mar;36(3):205-12. [PubMed]
3. DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol. 1998 Jun-Jul;38(2-3):245-52. [PubMed]
4. Shapiro WR, Young DF, Metha BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med. 1975 Jul 24;293(4):161-6. [PubMed]
5. Sandberg DI, Bilsky MH, Souweidane MM, Bzdil J, Gutin PH. Ommaya reservoirs for the treatment of leptomeningeal metastases. Neurosurgery. 2000 Jul;47(1):49-54; discussion 54-5. [PubMed]
6. Bleyer WA, Pizzo PA, Spence AM, et al. The Ommaya reservoir: newly recognized complications and recommendations for insertion and use. Cancer. 1978 Jun;41(6):2431-7. [PubMed]
7. Bleyer WA, Poplack DG. Intraventricular versus intralumbar methotrexate for central-nervous-system leukemia: prolonged remission with the Ommaya reservoir. Med Pediatr Oncol. 1979;6(3):207-13. [PubMed]
8. Peylan-Ramu N, Poplack DG, Pizzo PA, Adornato BT, Di Chiro G. Abnormal CT scans of the brain in asymptomatic children with acute lymphocytic leukemia after prophylactic treatment of the central nervous system with radiation and intrathecal chemotherapy. N Engl J Med. 1978 Apr 13;298(15):815-8. [PubMed]
9. Pääkkö E, Harila-Saari A, Vanionpää L, et al. White matter changes on MRI during treatment in children with acute lymphoblastic leukemia: correlation with neuropsychological findings. Med Pediatr Oncol. 2000 Nov;35(5):456-61. [PubMed]
10. Uldry PA, Teta D, Regli L. [Focal cerebral necrosis caused by intraventricular chemotherapy with methotrexate]. Neurochirurgie. 1991;37(1):72-4. [PubMed]
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