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Year : 2022  |  Volume : 20  |  Issue : 3  |  Page : 194-197

Chemotherapy-induced acute reversible toxic leukoencephalopathy

1 Department of Radiology, VPS Lakeshore Hospital, Kochi, Kerala, India
2 Department of Internal Medicine and Rheumatology, VPS Lakeshore Hospital, Kochi, Kerala, India
3 Department of Medical Oncology, VPS Lakeshore Hospital, Kochi, Kerala, India

Date of Submission22-Feb-2022
Date of Decision09-Apr-2022
Date of Acceptance01-May-2022
Date of Web Publication01-Aug-2022

Correspondence Address:
Dr. Muhammed Jasim Abdul Jalal
Department of Internal Medicine and Rheumatology, VPS Lakeshore Hospital, Nettoor. P. O., Maradu, NH 47 – Byepass, Kochi - 682 040, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cmi.cmi_24_22

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Acute toxic leukoencephalopathy can be due to a variety of endogenous and exogenous agents. Chemotherapy-induced toxic leukoencephalopathy is often encountered in clinical practice with the widespread use of various chemotherapeutic agents. Since initial clinical findings may be nonspecific, magnetic resonance imaging can be useful in the pattern recognition of white matter injury as well as to rule out its close differentials. Early diagnosis is important since prompt removal of the inciting agent and supportive therapy can reverse this condition, while delay can result in a poor prognosis. Here, we report a case of chemotherapy-induced toxic leukoencephalopathy in a patient with metastatic adenocarcinoma of the rectum from an imaging perspective.

Keywords: 5-fluorouracil, acute toxic leukoencephalopathy, diffusion-weighted imaging, excitotoxicity

How to cite this article:
Vishnu A K, Pratap T, Jacob D, Jalal MJ, Gopalakrishnabhakthan A. Chemotherapy-induced acute reversible toxic leukoencephalopathy. Curr Med Issues 2022;20:194-7

How to cite this URL:
Vishnu A K, Pratap T, Jacob D, Jalal MJ, Gopalakrishnabhakthan A. Chemotherapy-induced acute reversible toxic leukoencephalopathy. Curr Med Issues [serial online] 2022 [cited 2023 Mar 22];20:194-7. Available from: https://www.cmijournal.org/text.asp?2022/20/3/194/352972

  Introduction Top

Toxic leukoencephalopathy refers to a spectrum of diseases that injures the white matter on exposure to leukotoxic agents. These agents can be exogenous or endogenous, and the onset of these diseases can be acute or chronic. Common exogenous leukotoxic agents include therapeutic and drugs of abuse, radiation, and carbon monoxide poisoning. Endogenous agents such as hyperammonemia and hyperglycemia are also implicated in toxic leukoencephalopathy. With the advent of widespread use of chemotherapeutic and immunosuppressants, drug-induced acute toxic leukoencephalopathy (ATL) is commonly encountered in clinical practice. Magnetic resonance imaging (MRI) has an important role in making the diagnosis of ATL, ruling out its close differentials, and assessing the reversibility of the condition.

  Case Report Top

A 56-year-old male patient who was a known case of adenocarcinoma rectum with lung and liver metastasis presented to the emergency department on day 15 of the third cycle of FOLFOX (Folinic acid + Fluorouracil + Oxaliplatin) with the complaints of altered sensorium and slurring of speech since 6 h. Last infusion was given 4 days prior to the symptom onset. The patient was conscious, oriented, obeying oral commands, and was afebrile. The patient was initially on CAPOX (Capecitabine + Oxaliplatin), which was changed to FOLFOX after one cycle due to intolerance.

On examination, there were right upper motor neuron facial palsy and left plantar extensor response. He was moving all four limbs with grade 3–4 power. Speech output was decreased. There was no evidence of any mucositis. Total and differential counts were normal. Blood sugar, serum electrolytes, liver function tests, and renal function tests were also within normal limits. Electrocardiogram and echocardiogram was also normal. Initial clinical differential diagnosis was ischemic stroke with Broca's aphasia, posterior reversible encephalopathy syndrome (PRES), and toxic encephalopathy. Further evaluation was done with MRI of the brain.

MRI showed confluent, symmetric T2 hyperintense signal involving the bilateral periventricular white matter, splenium, and genu of corpus callosum as well as bilateral corticospinal tract with extension along the posterior limbs of internal capsule up to the bilateral crus cerebri. There was also symmetrical involvement of the middle cerebellar peduncles. The subcortical U fibers, basal ganglia, and cortical gray were spared. There was associated diffusion restriction in all these areas [Figure 1]a and [Figure 1]b. There was no evidence of blooming on T2 *-weighted sequences nor was there any abnormal contrast enhancement [Figure 2]. Fluid-attenuated inversion recovery (FLAIR) [Figure 3] showed only subtle high signal corresponding to the T2 hyperintensities. Time of flight angiogram showed normal signal in the intracranial and neck arteries [Figure 4].
Figure 1: Diffusion-weighted images (a) and corresponding ADC maps (b) showing areas of diffusion restriction in the corpus callosum (asterix), bilateral deep white matter (dot), posterior limbs of internal capsule (arrow head), and the middle cerebellar peduncle (arrow).

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Figure 2: T2-weighted image [Figure 2] shows subtle diffuse hyperintense signal along the areas of diffusion restriction.

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Figure 3: Axial FLAIR sequence shows subtle hyperintensity in the involved white matter tracts. This is unlike other conditions like PRES where the FLAIR changes are more distinct and early in the course of disease. PRES: Posterior reversible encephalopathy syndrome, FLAIR: Fluid-attenuated inversion recovery.

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Figure 4: Postcontrast images show absent contrast enhancement along the white matter tracts.

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The possibility of ATL was considered first in view of the confluent symmetric white matter signal change with diffusion restriction and correlating with the presence of an exogenous inciting factor of chemotherapy. Intravenous infusion of 5-fluorouracil (5-FU) in the FOLFOX regime was considered the possible etiology considering its predisposition to cause leukoencephalopathy and since central nervous system symptoms were not present during the initial CAPOX regime. Oral Capecitabine in the CAPOX regime is eventually converted to 5 FU, but drug-induced toxicity is very rare with oral preparations.

PRES was considered less likely since it usually presents with a leukocortical distribution of T2 high signal without any diffusion restriction. Hypoxic-ischemic encephalopathy was ruled out in view of the absence of cortical and deep gray involvement. Furthermore, echocardiogram was normal, and there was no history of any documented period of hypoxia. Since metabolic profile was normal, and in view of the spared basal ganglia and thalami, metabolic encephalopathies were also considered less likely. Stroke with aphasia was also ruled out due to the diffuse white matter involvement.

The patient improved on discontinuation of chemotherapy and supportive treatment. He was re-imaged with an MRI after 10 days, which showed total resolution of the white matter abnormalities [Figure 5]. There was also complete neurological recovery with resolution of right UMN facial palsy. Grade 4 power was recorded in all limbs. Subsequently, a further 5-FU was withheld and a modified dose of CAPOX 2-weekly was given. The patient tolerated this regime well on 2-month follow-up.
Figure 5: Diffusion-weighted images (a) and corresponding ADC maps (b) of the same patient on follow-up showing marked resolution in the abnormal diffusion along the periventricular white matter.

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  Discussion Top

Imaging manifestations of ATL can be correlated with the underlying pathophysiology. Although the mechanisms may be multifactorial such as direct myelin injury, capillary endothelial injury, or a combination of these, excitotoxicity is considered the usual final pathway.

Excitotoxicity refers to the excessive release of glutamate from the synaptic clefts in response to an insult. Although such an excitotoxic response is also implicated in ischemia, in toxic leukoencephalopathy, reuptake of the excessive glutamate is not affected. This results in intramyelinic edema where there is fluid accumulation between myelin layers without causing cell death which also explains the reversibility of ATL. Since reuptake of glutamate is impaired in ischemia, there is progressive cell swelling and cell death, becoming an irreversible condition.

On imaging, like cytotoxic edema, intramyelinic edema also shows diffusion restriction since the space between the myelin layers is extracellular, and fluid accumulation in these spaces will, in turn, restrict diffusion of water molecules to other extracellular spaces. Distinguishing factor from cytotoxic edema and intramyelinic edema is the reversibility and the characteristic distribution of the latter.[1]

Pattern recognition of ATL is important since it is a pointer toward its reversibility. Most cases show a characteristic symmetric or asymmetric confluent T2 high signal and diffusion restriction along the periventricular white matter and splenium with sparing of the subcortical U fibers, cortical and the deep gray matter. Such a pattern also correlates with the higher metabolism in these areas which predisposes them to excitotoxicity.[2]

Another characteristic diagnostic pointer are the changes in FLAIR sequence which are often subtle and not proportionate to the changes on T2-weighted sequence initially which may however become more prominent later. This is unlike conditions like PRES which shows early FLAIR changes.[3] Although there are differences in the extent of white matter involvement and ADC ratios across different etiologies of ATL, none of the imaging markers have shown a correlation with the clinical outcome which also adds to the need for early diagnosis.

Intramyelinic edema on MRI can occur with many inciting agents such as chemotherapeutic drugs, immunosuppressants, carbon monoxide poisoning, opioid abuse as well as in metabolic conditions like acute hepatic encephalopathy and uremia.[2] Common leukotoxic chemotherapeutic agents include methotrexate, 5-FU, fludarabine, vincristine, and cisplatin of which 5-FU and methotrexate are the mot common.[4] The most common pattern of chemotherapy-induced leukoencephalopathy is as confluent symmetric or asymmetric periventricular white matter hyperintensity and true diffusion restriction with sparing of subcortical U fibres, as previously described.[5]

5 FU is the most common chemotherapeutic agent associated with a dose-dependent ATL, classical imaging pattern being diffuse periventricular white matter involvement.[6],[7] Reversible splenial T2/FLAIR hyperintensities are also described.[8] Deficiency of dihydropyrimidine dehydrogenase (DPD) which is involved in pyrimidine metabolism is considered a risk factor for leukotoxicity, and therefore, pretreatment screening for DPD deficiency may be helpful in identifying patients at risk. Serum uracil and thymidine are characteristically elevated in DPD deficiency.[9] DPD genetic testing was done in our patient pretreatment; however, the results were favorable for normal metabolizer, and hence, normal drug dosage was advised. This highlights the possibility of ATL being an idiosyncratic reaction rather than a dose-dependent side effect. Although 5-FU toxicity is more common in the intermediate period after infusion, delayed neurotoxicity can also occur, as in our case.[10]

Compared to oral capecitabine, overall toxicity is more for intravenous 5 FU infusion.[11] Although oxaliplatin and capecitabine can cause ATL, they are relatively rare. However, there are certain reports which suggest that leukotoxicity is more when 5-FU and oxaliplatin are used in combination.

Early diagnosis and removal of the toxic agent are the only treatment required for ATL. Establishing a temporal relationship between a known inciting agent to the clinical symptoms along with a periventricular pattern in MRI is paramount in the diagnosis of this condition.

  Conclusion Top

Chemotherapy-induced ATL should be kept in mind during the evaluation of an oncological patient with rapid-onset neurological dysfunction. Recognition of the characteristic periventricular pattern on MRI can point toward the reversibility of ATL and to rule out its close differentials.

Informed consent

Informed written consent was obtained from the guardian of the patient for publishing the case details in a journal.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Al Brashdi YH, Albayram MS. Reversible restricted-diffusion lesion representing transient intramyelinic cytotoxic edema in a patient with traumatic brain injury. Neuroradiol J 2015;28:409-12.  Back to cited text no. 1
Rimkus Cde M, Andrade CS, Leite Cda C, McKinney AM, Lucato LT. Toxic leukoencephalopathies, including drug, medication, environmental, and radiation-induced encephalopathic syndromes. Semin Ultrasound CT MR 2014;35:97-117.  Back to cited text no. 2
Bartynski WS. Posterior reversible encephalopathy syndrome, Part 1: Fundamental imaging and clinical features. AJNR Am J Neuroradiol 2008;29:1036-42.  Back to cited text no. 3
Sioka C, Kyritsis AP. Central and peripheral nervous system toxicity of common chemotherapeutic agents. Cancer Chemother Pharmacol 2009;63:761-7.  Back to cited text no. 4
Inaba H, Khan RB, Laningham FH, Crews KR, Pui CH, Daw NC. Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol 2008;19:178-84.  Back to cited text no. 5
Choi SM, Lee SH, Yang YS, Kim BC, Kim MK, Cho KH. 5-fluorouracil-induced leukoencephalopathy in patients with breast cancer. J Korean Med Sci 2001;16:328-34.  Back to cited text no. 6
Paul BS, Singh G, Bansal R, Paul G. Diffusion weighted MR imaging of 5-fluorouracil and oxaliplatin-induced leukoencephalopathy. J Postgrad Med 2013;59:135-7.  Back to cited text no. 7
  [Full text]  
Acharya G, Cruz Carreras MT, Rice TW. 5-FU-induced leukoencephalopathy with reversible lesion of splenium of corpus callosum in a patient with colorectal cancer. BMJ Case Rep 2017;2017:bcr2017222030.  Back to cited text no. 8
Akitake R, Miyamoto S, Nakamura F, Horimatsu T, Ezoe Y, Muto M, et al. Early detection of 5-FU-induced acute leukoencephalopathy on diffusion-weighted MRI. Jpn J Clin Oncol 2011;41:121-4.  Back to cited text no. 9
Kwon KA, Kwon HC, Kim MC, Kim SH, Oh SY, Lee S, et al. A case of 5-fluorouracil induced encephalopathy. Cancer Res Treat 2010;42:118-20.  Back to cited text no. 10
Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 2001;19:2282-92.  Back to cited text no. 11


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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