Shilpa Jain, MD Ay-Ming Wang, MD Anant Krishnan, MD Ranjit K Jain , MD Kathleen Barry, MD

1. EP-48 MR Perfusion and MR Spectroscopy in Methotrexate induced Brain Parenchymal Necrosis relating to Indwelling Ventricular Catheter: A valuable tool in distinguishing from recurrent tumor Shilpa Jain, MD Ay-Ming Wang, MD Anant Krishnan, MD Ranjit K Jain , MD Kathleen Barry, MD Richard Silbergleit, MD Beaumont Health System, Royal Oak, MI Oakland University William Beaumont School of Medicine

2. Financial Disclosure The authors do not have any financial disclosures

3. Purpose • To illustrate MR imaging findings, MR perfusion and MR Spectroscopy features in two cases, that help to differentiate chemotherapy induced necrosis from tumor recurrence or progression • To discuss the probable physiology and predisposing factors affecting development of methotrexate induced brain parenchymal necrosis around indwelling ventricular catheters

4. CASE 1 • 40 year old female with history of stage IV carcinoma of the breast presented with headaches and difficulty walking • MRI of the brain was requested

5. July, 2013 MRI Brain with contrast: Multiple tiny enhancing lesions in the subcortical location in the left parietal lobe and in left periventricular white matter (red arrows). Corresponding increased FLAIR signal (yellow arrows) Axial FLAIR Axial FLAIR Axial T1 Axial T1C+ Axial T1C+

6. For the treatment of brain metastasis, whole brain radiation was started at an outside institution, but she received 27 Gy instead of planned 30 Gy due to progression of intracranial disease • She revisited our hospital after 1 month with worsening lower extremity weakness and pain. Brain MRI demonstrated improvement in cerebral metastasis • Ommaya reservoir was placed for intrathecal administration of methotrexate. Oral capecitabine was also administered

7. After 4 months, patient started having confusion, behavioral changes and worsening stability CT and MRI of the brain was requested Brain CT. Diffuse white matter hypodensity (yellow arrow) surrounding the Ommaya catheter in the right frontal lobe

8. January, 2014 MRI Brain: New peripherally enhancing area (red arrows) in the right frontal lobe, extending to genu of the corpus callosum along the catheter tract associated with diffusion restriction (green arrow). Surrounding diffuse increased FLAIR signal (yellow arrow) DWI Axial FLAIR Axial T2 Sagittal T1C+ Coronal T1C+ Axial T1C+

9. On the basis of MRI Brain findings, concern for infection versus metastatic disease was raised • CSF culture from catheter tip showed coagulase negative gram positive cocci • The Ommaya reservoir was removed, due to concern of infection and full course of antibiotics was completed • 1 week later, patient was found to be more lethargic and confused • A follow up MRI demonstrated increasing size of the mass • As coagulase negative Staph aureus do not typically cause brain abscesses, a repeat MRI brain with MR perfusion, MR spectroscopy was requested to evaluate for progression of the metastasis

10. February, 2014 Axial T1C+ FLAIR Axial T1C+ MRI Brain: Increasing size of the irregular peripheral enhancement along the removed catheter course in the right frontal lobe, genu and body of the corpus callosum (red arrows). Associated increased surrounding FLAIR signal (yellow arrow). Coronal T1C+ Coronal T1C+

11. rCBF( leakage corrected) rCBV (leakage corrected) rCBF ( leakage corrected) rCBV (leakage corrected) Dynamic susceptibility weighted contrast enhanced MR perfusion: The regional cerebral blood volume (rCBV) and regional cerebral blood flow (rCBF) in the majority of the lesion (arrow) in the right frontal lobe, and near genu of corpus callosum is not increased and in some regions is decreased as compared to normal contralateral brain parenchyma.

12. Contralateral normal brain Abnormal side Single voxel Spectroscopy: Decreased choline in (a) and (b) in the rim enhancing lesion in right frontal lobe. Though choline appears relatively elevated in (b), it is still less than the corresponding contralateral brain parenchyma (absolute value choline of 9.6 vs 12.8 on normal side). Pronounced decrease in NAA, some decrease in creatine and prominent lipid /lactate peaks in (a) and (b) TE 30 msec (a) TE 30 msec (c) TE 135 msec (b) TE 135 msec (d)

13. Summary of MR Imaging Findings • Enhancing mass around the catheter tract demonstrated decreased MR perfusion and decreased metabolites (except lipid) as compared to normal brain parenchyma • Elevated lipid peak can be seen with tumor necrosis, abscess or chemotherapy induced necrosis. However low choline makes tumor progression unlikely • Coagulase negative staphylococcus have low virulence and do not cause brain abscess. Additionally, antibiotics coverage did not improve patient symptomatically • Thus taking into account the clinical history, MR perfusion and spectroscopy findings, focal severe necrosis due to methotrexate toxicity was considered the most favorable diagnosis, likely aggravated by prior whole brain radiation • Unfortunately, patient’s condition was very poor and deteriorated and she was transferred to hospice

14. CASE 2 40 year old female with history of breast cancer, status post mastectomy, chemotherapy and chest wall radiation presented with headache and leg pain MRI of the brain and spine was ordered

15. March, 2014 MRI Brain: Enhancing nodule in right cerebellar hemisphere (green arrows). Normal supratentorial brain Axial T1C+ Axial T1C+ MRI Lumbar spine: Enhancing lesions in cauda equina nerve roots (red arrows), suggesting leptomeningeal metastasis Sagittal T1C+ Sagittal T2

16. Patient was diagnosed with leptomeningeal metastasis • She received fractionated radiation of 30 Gytotal dose to whole brain and similar dose to lumbar spine • Ommaya reservoir was subsequently placed for intrathecal methotrexate administration • She received 8 cycles of intrathecal chemotherapy • During last injection of chemotherapy, she developed nausea and vomiting and worsening headache • Subsequently, non contrast CT head was requested

17. July, 2014 Noncontrast CT Head: New right sided subdural hematoma (green arrow) with midline shift. Diffuse white matter hypodensity (red arrow) in right frontal lobe, surrounding the ventricular catheter Catheter was found to be malfunctioning as fluid could not be drained from it CSF study was negative for any infection Patient’s mental status deteriorated and was taken to operating room for drainage of the subdural hematoma and removal of the malfunctioning catheter MRI brain, MR perfusion and MR Spectroscopy was requested to differentiate tumor progression/recurrence from other possible causes

18. MRI Brain was performed after removal of the catheter (September 2014) DWI ADC Axial FLAIR Axial T2 Axial T1 Sagittal T1C+ Axial T1C+ Coronal T1C+ MRI Brain: T1 and T2 isointense (blue and green arrows) peripherally rim enhancing lesion in the right frontal lobe (red arrows), extending to the genu of the corpus callosum and along the tract of the previous ventricular catheter, associated with mild diffusion restriction (white arrow). Diffuse surrounding vasogenic edema (yellow arrow).

19. Axial rCBF (leakage corrected) Axial rCBV (leakage corrected) Dynamic susceptibility weighted contrast enhanced MR perfusion: Significant decrease of regional cerebral blood volume (rCBV) (red arrow) and regional cerebral blood flow (rCBF) (yellow arrow) in the rim enhancing lesion as compared to contralateral normal brain parenchyma

20. Contralateral normal brain Lesion Multivoxel MR Spectroscopy: Significant decrease in NAA and Cr peaks and mild decrease in choline peak in the rim enhancing area (a and c), as compared to contralateral normal brain parenchyma (b and d). Markedly elevated lipid peak in the center of rim enhancing area (a and c) (red arrows) . Normal contralateral brain parenchyma (c and d). TE 30 msec (a) TE 30 msec (b) TE 135 msec (c) TE 135 msec (d)

21. Summary of MR Imaging findings • Decreased perfusion and diffuse reduction of metabolites in the rim enhancing lesion along the tract of the removed catheter favoring cell death rather than tumor progression • Elevated lipid peak suggesting necrosis • Infection was considered less likely as CSF culture was negative • Thus chemotherapy induced necrosis was considered the most favorable diagnosis, aggravated by malfunctioning catheter and whole brain radiation • Patient’s neurological condition slowly improved and the abnormal enhancement on brain MRI diminished on follow up imaging

22. Ommaya Catheters and Chemotherapy • Leptomeningeal metastasis is commonly found in patients with melanoma, breast cancer, lung cancer, leukemia, most common being breast cancer • Intrathecal chemotherapy is the most effective treatment for meningeal carcinomatosis • Methotrexate, cytarabine, and thiopetaare most commonly used in intrathecal chemotherapy • Ommaya reservoirs and repeat lumbar punctures are primary means of delivering intrathecal chemotherapy

23. Advantages of Ommaya reservoir placement over repeat lumbar puncture: -Improved patient comfort -Diminished risk for patients with thrombocytopenia -More consistent drug levels -Possibly greater clinical efficacy • Complications of Ommaya reservoir placement: Related to placement : malposition, hemorrhage, infection Related to its use: Asymptomatic white matter changes Pericatheter leukoencephalopathy (2-40%)

24. Factors affecting the development of leukoencephalopathy: -Total dosage of drug administrated -Pre-sensitization by whole-brain irradiation -Treatment with intravenous methotrexate -Malfunctioning/malposition catheters -Increased intraventricular pressure • Pathophysiology: Presence of distal obstruction or increased CSF pressure transependymal diffusion retrograde flow of CSF around the catheter into the adjacent brain parenchyma This can be noted months to years after intraventricular chemotherapy administration Partial or complete resolution of the lesion after removal /revision of the catheter: partial resolution may be observed in 4±8 weeks and complete resolution in 1±15 months

25. Conclusion • Intraventricular catheters are frequently used to deliver chemotherapy such as methotrexate in cancer patients with leptomeningeal metastasis • They can cause necrosis around the catheter tract, the incidence of which increases from prior sensitization of the brain by radiation • The appearance of necrosis on routine brain MRI may be confused with tumor recurrence • MR perfusion and MR spectroscopy can help solve the problem by demonstrating lack of increased blood volume, flow and decreased metabolites, features distinguishing it from tumor progression • Awareness of this complication in patients with indwelling catheters is critical, as it may be reversible, and it is important for the neuroradiologist to consider spectroscopy and perfusion for confirmation

26. Reference • Hara H, Igarashi A, Yano Y, et al. Interventricular methotrexate therapy for carcinomatous meningitis due to breast cancer: A case with Leukoencephalopathy. Breast Cancer 2000:7(3):247-51 • Sandberg DI, Bilsky MH, Souweidane MM, et al. Ommaya reservoirs for the treatment of leptomeningeal metastasis. Neurosurgery 2000:47(1):49-55 • Stone JA, Castillo M, Mukherji SK. Leukoencephalopathy complicating an Ommaya reservoir and chemotherapy. Neuroradiology 1999:41:134- 136. • Gowan GM, Herrington JD, Simonetta AB. Methotrexate-induced toxic leukoencephalopathy. Pharmocotherapy 2002:22(9):1183-1187. • Pande AR, Ando K, Ishikura R et al. Disseminated necrotizing leukoencephalopathy following chemoradiation therapy for acute lymphoblastic leukemia. Radiat med 2006: Aug;24(7):515-9.

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