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|Year : 2013 | Volume
| Issue : 2 | Page : 135-137
Diffusion weighted MR imaging of 5-fluorouracil and oxaliplatin-induced leukoencephalopathy
BS Paul1, G Singh1, R Bansal1, G Paul2
1 Department of Neurology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
2 Intensive Care Unit, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
|Date of Submission||08-Jul-2012|
|Date of Decision||09-Dec-2012|
|Date of Acceptance||20-Feb-2013|
|Date of Web Publication||21-Jun-2013|
B S Paul
Department of Neurology, Dayanand Medical College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
A 55-year-old man treated with 5-fluorouracil and oxaliplatin for advanced sigmoid colon cancer presented with seizures, progressive gait and balance difficulties with frequent falls and slurring of speech. After three cycles of chemotherapy, brain magnetic resonance imaging using diffusion-weighted imaging clearly revealed the presence of high signal intensity in the deep white matter of the bilateral cerebral hemispheres, including the corpus callosum symmetrically. A diagnosis of acute leukoencephalopathy was made based on these findings. His clinical symptoms normalized after the discontinuation of the chemotherapy. Early detection of drug-induced leukoencephalopathy is important as the clinical symptoms can be reversed by early discontinuation of the causative drug. Diffusion-weighted magnetic resonance imaging is a useful modality for the early detection and definitive diagnosis of this characteristic encephalopathy.
Keywords: Acute leukoencephalopathy, 5-fluorouracil, magnetic resonance-diffusion weighted imaging, oxaliplatin
|How to cite this article:|
Paul B S, Singh G, Bansal R, Paul G. Diffusion weighted MR imaging of 5-fluorouracil and oxaliplatin-induced leukoencephalopathy. J Postgrad Med 2013;59:135-7
|How to cite this URL:|
Paul B S, Singh G, Bansal R, Paul G. Diffusion weighted MR imaging of 5-fluorouracil and oxaliplatin-induced leukoencephalopathy. J Postgrad Med [serial online] 2013 [cited 2019 Jun 20];59:135-7. Available from: http://www.jpgmonline.com/text.asp?2013/59/2/135/113845
| :: Introduction|| |
Leukoencephalopathy is a cerebral demyelinating syndrome, mostly related to chemotherapeutic drugs. Though rare, it can present as confusion, seizure, ataxia, motor deficits and even deep coma. Toxic leukoencephalopathy is sometimes known to reverse clinically, if the offending agent is stopped before irreversible damage occurs.  Diffusion-weighted magnetic resonance (DW-MR) is a useful modality for early detection and definitive diagnosis of the syndrome. ,
To the best of our knowledge, only a few cases have been reported to date in literature. We report this unique case, in which there was extensive involvement of subcortical white matter with diffusion restriction which has not been reported earlier.
| :: Case Report|| |
A 55-year-old man was diagnosed to have sigmoid colon carcinoma , underwent resection. Post operatively chemotherapy was instituted with 5-fluorouracil (FU) and Oxaliplatin. On Day 1, he received Oxaliplatin 85 mg/m 2 and leucovorin 200mg/m 2 intravenously over 120 minutes followed by 5-FU 400 mg/m 2 over 2-4 minutes and 5-FU 600 mg/m 2 as a 22 hour infusion. On Day 2, he received leucovorin 200mg/m 2 intravenously over 120 minutes followed by 5-FU 400 mg/m 2 over 2-4 minutes and later 5-FU 600 mg/m 2 as a 22 hour infusion. This cycle was repeated every 2 weeks. After the third cycle of chemotherapy, his family members noted progressive gait difficulties associated with frequent falls and slurring of speech. Three days later, he presented with an episode of generalized tonic clonic seizures to the emergency department.
On examination, the patient was conscious and well oriented. The blood pressure was normal. Neurologic examination showed a well-oriented person with normal cranial nerve and motor system examination. His sensory system examination was also normal. There was evidence of bilateral symmetrical cerebellar signs with gait ataxia and dysarthria. Laboratory evaluation showed complete blood count, electrolytes, liver and renal functions within normal limits. The cerebrospinal fluid contained two lymphocytes per milliliter and 56 mg of protein per decilitre, rest of the work up was normal. Electroencephalogram showed mild generalized dysrhythmia.
A Magnetic resonance imaging (DW weighted) of the brain was then done that showed significant diffusion restriction [Figure 1]a-c in the frontal, parietal, subcortical white matter bilaterally and the splenium of the corpus callosum. Apparent diffusion coefficient (ADC) image corresponding to the DW sequence also showed acute diffusion restriction [Figure 2]a and b, as evident by the dark signal in the region of reduced diffusion and T2 sequence [Figure 3]. No abnormal enhancement was seen on contrast.
|Figure 1: MRI Axial diffusion‑weighted image shows significant restriction of diffusion in (a) the splenium of the corpus callosum; (b) in the subcortical white matter and U‑fibres (c) in the bilateral symmetrical white matter|
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|Figure 2: ADC image shows diffusion restriction, as evident by the dark signals (a) in the region of corpus callosum and white matter tracts; (b) in the subcortical white matter and U fibres|
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|Figure 3: T‑2 weighted sequence showing hyper intense signal change in subcortical white matter|
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A diagnosis of acute leukoencephalopathy was made based on these clinical and radiological findings. Chemotherapy was stopped and pulse of methypredisolone was given for three days following which he made gradual recovery in his gait ataxia. In next 3 weeks, he made complete recovery with no residual signs such that he started walking independently.
| :: Discussion|| |
Leukoencephalopathy initially manifests itself as dizziness, numbness, disorientation, memory deficit, confusion, agitation, cognitive impairment and unsteady gait. In severe cases, stupor, seizure, akinetic mutism and even coma may occur.  Drug-induced leukoencephalopathy is mainly caused by chemotherapeutic agents that include methotrexate, vincristine, ifosfamide, fludarabine, cytarabine, 5-FU, cisplatin, and the interferons.  Among them, 5-FU has been reported most frequently as a causative agent of the syndrome. The vast majority of case reports describing leukoencephalopathy are associated with 5-FU and levamisole when used in combination.  5-FU is a fluorine-substituted analogue of pyrimidine uracil. However, 5-FU-induced neurotoxicity is uncommon and has an incidence of less than 5% among patients treated with this agent. Oxaliplatin induced neurotoxicity is rarely reported with incidence of <1%. It was difficult to find out which chemotherapeutic drug had caused the leukoencephalopathy though previous reports suggest the most common agent is 5-FU. We thought that the combined use of both 5-FU and oxaliplatin may have led to more severe and wide spread white matter changes and leukoencephalopathy.
Dihydropyrimidine dehydrogenase (DPD) is responsible for more than 85% of the catabolism of pyrimidine. Several studies suggest that DPD deficiency, in which the serum and urine levels of uracil and thymidine are increased, may be a risk factor for 5-FU-induced leukoencephalopathy.  It has been reported that DPD deficiency occurs in upto 3% of the adult cancer patients which may be asymptomatic prior to the chemotherapy. Thus, these patients are at increased risk for severe adverse reactions. 
The common radiological imaging findings of leukoencephalopathy include symmetrical periventricular high intensity signal in the white matter and corpus callosum on T2 weighted and DW-MRI. DW-MRI is more sensitive for the detection of abnormalities in the white matter.  In the present case, the presence of symmetrical high signal intensity in the deep white matter of the bilateral cerebral hemispheres, including the corpus callosum was clearly seen, which was consistent with drug-induced leukoencephalopathy.
To the best of our knowledge, only a few cases of reversible posterior leukoencephalopathy syndrome (RPLS) induced by 5-FU and oxaliplatin have been reported. In literature, such extensive white matter involvement as seen in our patient has not been reported. Although the exact cause of diffusion restriction is not known, but we presume that it is due to either intramyelinic edema (myelin vacuolation), cytotoxicity due to endothelial damage, or due to direct toxic demyelination that makes this region susceptible to the accumulation of fluid in the extracellular spaces (vasogenic edema). 
Several treatment modalities have been proposed in the literature apart from purely supportive measures to the use of plasma exchange and thiamine.  We used methylprednisolone (1 gm) pulse therapy for 3 days in this patient in view of the extensive and symptomatic inflammatory encephalopathy which could have been secondary to vasogenic edema. Our patient showed marked clinical improvement after the treatment but repeat MR was not done as the patient refused consent.
The third learning point from our case was that age-related periventricular hyper intensity must be differentiated from drug-induced leukoencephalopathy. These T2-weighted and flow-sensitive alternating inversion recovery (FAIR) MRI findings are similar to those observed in drug-induced leukoencephalopathy. DW-MRI sequence can help the clinician in differentiating between the two.
| :: Acknowledgment|| |
We wish to thank our patient for cooperation and willingness for this publication.
| :: References|| |
|1.||Filley CM, Kleinschmidt-DeMasters BK.Toxic leukoencephalopathy. N Engl J Med 2001;345:425-32. |
|2.||Cheung WY, Fralick RA, Cheng S. The confused cancer patient: A case of 5-fluorouracil-induced encephalopathy. Curr Oncol 2008;15:234-6. |
|3.||Fujikawa A, Tsuchiya K, Katase S, Kurosaki Y, Hachiya J. Diffusion weighted MR imaging of Calmofur-induced leukoencephalopathy. Eur Radiol 2001;11:2602-6. |
|4.||Sioka C, Kyritsis AP. Central and peripheral nervous system toxicity of common chemotherapeutic agents. Cancer Chemothe rPharmacol 2009;63:761-7. |
|5.||Kimmel DW, Wijdicks EF, Rodriguez M. Multifocal inflammatory leukoencephalopathy associated with levamisole therapy. Neurology1995;45:374-6. |
|6.||Takimoto CH, Lu ZH, Zhang R, Liang MD, Larson LV, Cantilena LR Jr, et al. Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydroprymidine dehydrogenase deficiency. Clin Cancer Res1996;2:477-81. |
|7.||Hayashi K, Kidouchi K, Sumi S. Possible prediction of adverse reactions to pyrimidine chemotherapy from urinary pyrimidine levels and a case of asymptomatic adult dihydropyrimidinuria. Clin Cancer Res 1996;2:1937-41. |
|8.||Tha KK, Terae S, Sugiura M, Nishioka T, Oka M, Kudoh K, et al. Diffusion-weighted magnetic resonance imaging in early stage of 5-fluorouracil-induced leukoencephalopathy. ActaNeurol Scand 2002;106:379-86. |
|9.||Ito Y, Arahata Y, Goto Y, Hirayama M, Nagamutsu M, Yasuda T, et al. Cisplatin neurotoxicity presenting as reversible posterior leukoencephalopathy syndrome. Am J Neuroradiol 1998; 19:415-7. |
|10.||Pirzada NA, Ali II, Dafer RM. Fluorouracil-induced neurotoxicity. Ann Pharmacother 2000;34:35-8. |
[Figure 1], [Figure 2], [Figure 3]
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