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Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 105-107

Delirium and seizures in a patient with head-and-neck squamous cell carcinoma on docetaxel, cisplatin, and 5-fluorouracil

Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication9-Sep-2019

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_35_19

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A 33 year male, case of locally advanced carcinoma left buccal mucosa treated with docetaxel, cisplatin and 5-fluorouracil as neoadjuvant therapy developed acute onset delirium, seizures and agitation on fifth day of first cycle of chemotherapy. Although CT brain revealed no abnormality, MRI brain showed symmetric areas of diffusion restriction with T2/FLAIR hyperintensity involving periventricular region (lateral ventricles), centrum semiovale and corpus callosum. His clinical symptoms normalized after one week of stopping therapy. What is the diagnosis, and how should the patient be managed?

Keywords: 5-Fluorouracil, delirium, diffusion restriction, leukoencephalopathy, T2/FLAIR hyperintensity

How to cite this article:
Khaddar S, Patil VM, Noronha V, Joshi A, Menon N, Prabhash K. Delirium and seizures in a patient with head-and-neck squamous cell carcinoma on docetaxel, cisplatin, and 5-fluorouracil. Cancer Res Stat Treat 2019;2:105-7

How to cite this URL:
Khaddar S, Patil VM, Noronha V, Joshi A, Menon N, Prabhash K. Delirium and seizures in a patient with head-and-neck squamous cell carcinoma on docetaxel, cisplatin, and 5-fluorouracil. Cancer Res Stat Treat [serial online] 2019 [cited 2020 Aug 4];2:105-7. Available from: http://www.crstonline.com/text.asp?2019/2/1/105/266457

A 33-year-old male presented with an ulcerated lesion in the right buccal mucosa. He was a former tobacco chewer and alcoholic, abstinent for 5 years. On evaluation, he had a synchronous primary in the right buccal mucosa and left lateral border of the tongue, which were deemed to be borderline operable because of facial edema extending up to the zygoma, Stage IVB (AJCC TNM 8th edition cT4b N1 M0). He was started on neoadjuvant chemotherapy with docetaxel (75 mg/m 2 intravenously on day 1), cisplatin (75 mg/m 2 intravenously on day 1), and 5-fluorouracil (5-FU, 750 mg/m 2/day as a continuous intravenous infusion from day 1 to day 5), the DCF regimen. Testing did not reveal the presence of a mutation in the dihydropyrimidine dehydrogenase gene, and he was given full-dose chemotherapy. On the 5th day of the infusion, he developed acute-onset altered behavior in the form of decreased responsiveness, followed by one episode of seizure activity. Vital signs were normal; serum electrolytes and blood sugar levels were within the normal range. The 5-FU infusion was withheld. Computed tomography (CT) imaging of the brain revealed no abnormality. His blood lactate levels were greater than the measurable upper limit (normal: 0.5–1 mmol/L), and blood gas analysis revealed anion gap metabolic acidosis. He regained consciousness within 48 hours; however, he continued to have intermittent episodes of agitation. Contrast-enhanced magnetic resonance imaging (MRI) of the brain revealed symmetric areas of diffusion restriction with T2/ fluid-attenuated inversion recovery hyperintensity involving the periventricular region (lateral ventricles), centrum semiovale, and corpus callosum without any contrast enhancement [Figure 1] and [Figure 2]. He was managed conservatively and improved over 1 week. He was discharged in stable condition.
Figure 1: T2/Fluid-attenuated inversion recovery hyperintensity involving the periventricular region (lateral ventricles), centrum semiovale, and corpus callosum

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Figure 2: Diffusion-weighted imaging sequence showing diffusion restriction in corresponding areas of T2/fluid-attenuated inversion recovery hyperintensity

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What is the diagnosis?

Once you have finalized your answer to this challenge, please turn to page 106 to read on.

Drug-induced leukoencephalopathy is a potentially reversible phenomenon; therefore, early detection is important. Diffusion-weighted (DW) MRI is a useful tool for the early detection and definitive diagnosis of this characteristic encephalopathy.

5-FU is commonly used in the treatment of various solid tumors, including head and neck, breast, esophagus, stomach, intestine, and others. There have been case reports about the central nervous system toxicity of 5-FU.[1],[2],[3] Encephalopathy is a rare side effect which may manifest as agitation, confusion, seizures, stupor, or coma. Various predisposing factors have been reported for the development of leukoencephalopathy, including nausea, vomiting, constipation, or infection during chemotherapy. Our patient did not have any of these predisposing factors. DW MRI is useful for the detection of this toxic encephalopathy. Herein, we report a case of 5-FU-induced acute leukoencephalopathy.

Leukoencephalopathy can manifest can manifest as dizziness, as dizziness, disorientation, confusion, agitation, or cognitive impairment, and in severe cases, stupor, seizure, and even coma.[4] Common side effects of 5-FU are bone marrow suppression, gastrointestinal toxicities such as stomatitis, nausea, vomiting, and diarrhea. Drug-induced leukoencephalopathy is mainly caused by various chemotherapeutic agents, which include methotrexate, vincristine, ifosfamide, fludarabine, cytarabine, 5-FU, cisplatin, and the interferons.[5] Among them, 5-FU has been reported most frequently as a leukoencephalopathy causative agent. The specific mechanism of encephalopathy is not known. It has been postulated that myelin destruction may be responsible as elevated levels of myelin basic protein are seen in CSF in such cases.[6] In our case, cerebrospinal fluid examination was not performed.

The common radiological findings of leukoencephalopathy include symmetrical periventricular hypoattenuation on CT scan and diffuse high-intensity signal in the white matter and corpus callosum on T2-weighted MRI and DW-MRI. DW-MRI is more sensitive than CT scan for the detection of abnormalities in the white matter.[7],[8]

Drug-induced leukoencephalopathy is usually reversible, and the improvement of clinical symptoms after the withdrawal of the causative drug strongly supports the diagnosis of encephalopathy. Our patient's clinical symptoms normalized 1 week after stopping 5-FU therapy. The treatment modalities are not well-defined, and supportive measures as well as corticosteroids and thiamine have been used.[9],[10] Our patient had already received intravenous dexamethasone (8 mg) as premedication on day 1 and day 2 of chemotherapy. Aminophylline and methylene blue have been used in methotrexate- and ifosfamide-induced leukoencephalopathies, respectively; however, there is no such report of their use in 5-FU-induced leukoencephalopathy.[11],[12] There is no clear recommendation regarding the safety of re-challenging the patient with the chemotherapy drug, after the resolution of symptoms. In the published case reports, 5-FU was permanently discontinued after the development of leukoencephalopathy. In our patient as well, 5-FU was stopped, and the patient received docetaxel and cisplatin as neoadjuvant chemotherapy, without recurrence of encephalopathy.

In conclusion, the clinical observation of acute development of abnormal neurological findings in patients treated with chemotherapeutic agents (especially 5-FU) should lead to the consideration of a diagnosis of drug-induced leukoencephalopathy. DW-MRI can help to establish an early diagnosis, and prompt withholding of the suspected drug along with supportive care may reverse and prevent further neurological manifestations.

Declaration of patient consent

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

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Cheung WY, Fralick RA, Cheng S. The confused cancer patient: A case of 5-fluorouracil-induced encephalopathy. Curr Oncol 2008;15:234-6.  Back to cited text no. 2
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. 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.  Back to cited text no. 4
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. 5
Hayashi R, Hanyu N, Kitahara A. Leukoencephalopathy induced by tegafur: Serial studies of somatosensory evoked potentials and cerebrospinal fluid. Intern Med 1992;31:828-31.  Back to cited text no. 6
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. Acta Neurol Scand 2002;106:379-86.  Back to cited text no. 7
Mahajan A, Jain H, Simha V, Vaidya T, Kumar GV, Gupta A, et al. Clinical–radiological features of methotrexate-induced subacute leukoencephalopathy in patients with acute lymphoblastic leukemia: 'Panda eye sign' on diffusion weighted-magnetic resonance imaging. Cancer Res Stat Treat 2019;2:28-33.  Back to cited text no. 8
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Pirzada NA, Ali II, Dafer RM. Fluorouracil-induced neurotoxicity. Ann Pharmacother 2000;34:35-8.  Back to cited text no. 9
Cossaart N, Cruz KS, Preston D, Johnson P, Skikne BS. Fatal chemotherapy-induced encephalopathy following high-dose therapy for metastatic breast cancer: A case report and review of the literature. Bone Marrow Transplant 2003;31:57-60.  Back to cited text no. 10
Ganesan P, Bajpai P, Shah A, Saikrishnan P, Sagar TG. Methotrexate induced acute encephalopathy-occurrence on re-challenge and response to aminophylline. Indian J Hematol Blood Transfus 2014;30:105-7.  Back to cited text no. 11
Pelgrims J, De Vos F, Van den Brande J, Schrijvers D, Prové A, Vermorken JB, et al. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: Report of 12 cases and a review of the literature. Br J Cancer 2000;82:291-4.  Back to cited text no. 12


  [Figure 1], [Figure 2]


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