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CASE REPORT Table of Contents  
Ahead of print publication
Ifosfamide-induced extrapyramidal neurotoxicity with COVID-19

1 Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Anesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India
4 Critical and Intensive Care, Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi, India

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Date of Submission31-May-2022
Date of Decision08-Jul-2022
Date of Acceptance14-Jul-2022
Date of Web Publication31-Jan-2023


Ifosfamide, an analog of cyclophosphamide, is commonly used as a chemotherapeutic agent to treat sarcomas and solid tumors. However, neurotoxicity is a rare side effect of this drug. When present, the symptoms range from confusion, agitation, and delirium in mild cases to mutism, visual blurring, hallucinations, seizures, stupor, and even coma in extreme cases. Within this spectrum, extrapyramidal symptoms are extremely rare, and when present, may not revert with drug discontinuation. Sequelae may occasionally persist even after discontinuation of the drug. Our case illustrates a rare occurrence of ifosfamide-induced extrapyramidal neurotoxicity in a patient with metastatic phyllodes tumor of the breast and concomitant COVID-19 illness. Ifosfamide-induced extrapyramidal neurotoxicity is a clinical diagnosis of exclusion and requires ruling out of other possible causes. The diagnosis is supported by a temporal correlation with drug administration, presence of risk factors, and improvement after infusion cessation, along with normal brain imaging.

Keywords: extrapyramidal, ifosfamide, ifosfamide-induced extrapyramidal neurotoxicity, neurotoxicity

How to cite this URL:
Nagpal C, Agarwal A, Venkateswaran V, Soni KD, Srivastava MP, Trikha A. Ifosfamide-induced extrapyramidal neurotoxicity with COVID-19. Ann Mov Disord [Epub ahead of print] [cited 2023 Mar 23]. Available from: https://www.aomd.in/preprintarticle.asp?id=368617

  Introduction Top

Ifosfamide is a chemotherapeutic agent for sarcomas and solid tumors.[1] It rarely causes neurotoxicity, and extrapyramidal symptoms are even rare[2] [Table 1]. Ifosfamide-induced extrapyramidal neurotoxicity (IIEN) is a clinical diagnosis[3] supported by temporal correlation with drug administration, presence of risk factors, and improvement after cessation, with normal neuroimaging. Conservative management consists of drug discontinuation and metabolic correction, which reverses the symptoms in most patients.[1] In addition, active treatment with albumin, methylene blue, and thiamine has been advocated.[4] In this report, we present a case of IIEN with COVID-19.
Table 1: Previously published cases of ifosfamide-induced extrapyramidal neurotoxicity

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  Case Report Top

A 39-year-old woman with breast malignancy presented to our oncology center to receive her second cycle of chemotherapy (ifosfamide and adriamycin). Her prechemotherapy investigations were unremarkable. After premedication with intravenous dexamethasone, ondansetron, and fosaprepitant, she received an infusion of 5 g of ifosfamide (500 ml normal saline) over 1 hour, along with 1 gram mesna stat 4 and 8 hours later, and 50 mg of adriamycin (100 ml normal saline). This regimen was planned for two more days. Six hours after completion of day 1 of the infusion, the patient presented with altered sensorium; reduced verbal output; involuntary lip-smacking movements; and stiffness of limbs without fever, headache, or focal deficits. She had history of similar, mild symptoms after her first chemotherapy cycle.

Her Glasgow Coma Scale score was E4V1M5 (E, eye opening; V, verbal; and M, motor). She had rigidity in her limbs, bilateral flexor plantar, persistent perioral dyskinesias, normal pupils, and oxygen saturation of 96% on room air. Routine blood investigations were normal except for hypoalbuminemia (albumin, 2.3 mg/L) and hypokalemia (K+-2.1 mEq/L). Reverse transcription–polymerase chain reaction for COVID-19 was positive. Contrast-enhanced brain and chest magnetic resonance imaging were normal. In addition, her autoimmune, paraneoplastic, and vasculitic panels were negative.

Our patient was diagnosed with IIEN, and an objective causality assessment revealed the adverse drug reaction to be 10 (probable).[3] She was treated with intravenous fluids, 50-mg methylene blue every 4 hours, and 100-mg thiamine every 8 hours, along with correction of hypoalbuminemia and hypokalemia. Her symptoms resolved after 3 days, following which methylene blue and thiamine were discontinued. She was discharged 1 week later.

  Discussion Top

Neurotoxicity can occur in 10–40% of the patients receiving ifosfamide.[1] It is caused by metabolite accumulation, in particular, chloroacetaldehyde.[1],[2] The symptoms range from mild confusion to agitation, stupor, and coma. They develop over 12–16 hours and usually spontaneously reverse within 48–72 hours of drug discontinuation. Certain factors such as hypoalbuminemia, renal dysfunction, pelvic disease, hyponatremia, hypokalemia, administration as a shorter infusion, and increasing age[4],[5],[6] predispose patients to ifosfamide-induced neurotoxicity.

Our case presented two challenges: diagnosis of a rare phenomenon and alteration of disease management due to COVID-19. She had Meanwell grade 3 encephalopathy[4] with extrapyramidal features such as rigidity, perioral dyskinesias, and mutism. In addition, she had risk factors such as hypoalbuminemia and hypokalemia. There was a temporal correlation between drug administration and symptom onset along with positive past history and symptom resolution within 72 hours of management therapy. The other drugs administered are not usually associated with neurotoxicity.[7]

Although the treatment of IIEN primarily consists of drug discontinuation, some reports support treatment with albumin, methylene blue, and thiamine.[5],[6] Methylene blue reduces the duration of neurotoxicity and can be a secondary prophylactic agent for further doses[5]; however, it can cause hemolytic anemia and methemoglobinemia.[6]

To the best of our knowledge, there is no existing literature on ifosfamide-induced neurotoxicity with COVID-19. Extrapyramidal manifestations are extremely rare in COVID-19.[8] We do not suggest that the neurotoxicity in our patient was caused by COVID-19, but we believe that it was likely an incidental finding. However, since our patient was positive for COVID-19, some synergistic action cannot be ruled out with certainty. Patient outcome with this combination of illnesses is difficult to predict. Therefore, we decided to expedite her recovery from drug toxicity before COVID-19 manifested.

  Learning Points Top

  • (1) IIEN can occur, although its occurrence is rare

  • (2) The risk factors for IIEN include hypoalbuminemia, renal dysfunction, pelvic disease, hyponatremia, hypokalemia, administration as a shorter infusion, and increasing age

  • (3) Methylene blue may help hasten recovery from IIEN

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.



Author contribution

All authors contributed towards the idea, writing, editing and reviewing of the manuscript.

Ethical compliance statement

No author had any conflict of interest and there is no financial disclosure. Written informed consent was taken from the patient with regards to publication.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Sweiss KI, Beri R, Shord SS Encephalopathy after high-dose Ifosfamide. Drug Saf 2008;31:989-96.  Back to cited text no. 1
Anderson NR, Tandon DS Ifosfamide extrapyramidal neurotoxicity. Cancer 1991;68:72-5.  Back to cited text no. 2
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 3
Meanwell CA, Blake AE, Kelly KA, Honigsberger L, Blackledge G Prediction of ifosfamide/mesna associated encephalopathy. Eur J Cancer Clin Oncol 1986;22:815-9.  Back to cited text no. 4
Ajithkumar T, Parkinson C, Shamshad F, Murray P Ifosfamide encephalopathy. Clin Oncol R Coll Radiol G B 2007;19: 108-14.  Back to cited text no. 5
Abahssain H, Moukafih B, Essangri H, Mrabti H, Meddah B, Guessous F, et al. Methylene blue and ifosfamide-induced encephalopathy: Myth or reality? J Oncol Pharm Pract Off Publ Int Soc Oncol Pharm Pract 2021;27:143-9.  Back to cited text no. 6
Modi JN, Cimino SK Incidence of ifosfamide induced encephalopathy in patients receiving concomitant fosaprepitant. J Oncol Pharm Pract 2021;27:1891-5.  Back to cited text no. 7
Misra S, Kolappa K, Prasad M, Radhakrishnan D, Thakur KT, Solomon T, et al. Frequency of neurologic manifestations in COVID-19: A systematic review and meta-analysis. Neurology 2021;97:e2229-81.  Back to cited text no. 8

Correspondence Address:
Ayush Agarwal,
Department of Neurology, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None


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