500777 research-article2013

EEGXXX10.1177/1550059413500777Clinical EEG and NeuroscienceTaupin et al

Article

Ifosfamide Chemotherapy and Nonconvulsive Status Epilepticus: Case Report and Review of the Literature

Clinical EEG and Neuroscience 2014, Vol. 45(3) 222­–225 © EEG and Clinical Neuroscience Society (ECNS) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1550059413500777 eeg.sagepub.com

Daniel Taupin1, Rikki Racela2, and Daniel Friedman2

Abstract We present a patient with peritoneal carcinosarcoma who was treated with the alkylating agent ifosfamide and experienced a rapid decline in mental status. Electroencephalogram (EEG) displayed generalized periodic epileptiform discharges, which raised suspicion for nonconvulsive status epilepticus (NCSE). Following administration of midazolam, the patient’s clinical condition and EEG improved. We review the 8 documented cases of ifosfamide-induced NCSE, and demonstrate the similarity in clinical features when compared with ifosfamide neurotoxicity that is not classified as NCSE. EEG findings suggesting an ictal pattern are subtle and heterogeneous, but they are essential for a diagnosis. Since it is unlikely that EEGs are uniformly obtained in instances of ifosfamide neurotoxicity, many cases of NCSE may go unrecognized. Keywords status epilepticus, antineoplastic agents, ifosfamide, electroencephalography, epilepsy Received 16 April 2013; revised manuscript accepted 12 July 2013

Introduction Ifosfamide is an oxazaphosphorine alkylating agent that is approved for use in the treatment of malignant testicular germ cells tumors. It has also been shown to be effective as a single or combination therapy to treat a wide variety of sarcomas, carcinomas, and lymphomas.1 Like its isomer cyclophosphamide, adverse effects include myelosuppression, alopecia, and nausea. Additionally, both compounds produce the metabolite acrolein, which may cause hemorrhagic cystitis unless neutralized by concurrent administration of mesna (2-mercaptoethane sulfonate-Na). Unlike cyclophosphamide, which rarely causes neurologic problems, ifosfamide is associated with central nervous system (CNS) toxicity in 5% to 30% of patients.2 Signs and symptoms can include confusion, hallucinations, lethargy, mutism, personality changes, weakness, urinary incontinence, extrapyramidal symptoms and cerebellar disfunction.3 This CNS toxicity is often attributed to metabolic derangement, possibly stemming from the buildup of the metabolite chloroacetaldehyde and subsequent glutathione depletion, inhibition of fatty acid oxidation and mitochondrial toxicity.3 CNS symptom onset usually occurs 2 to 48 hours following initiation of ifosfamide3 and can remit spontaneously 24 to 72 hours following discontinuation of the drug.2 Administration of oral methylene blue and/or thiamine may prevent or reverse these symptoms.3,4 While metabolic encephalopathy may account for the CNS symptoms in many patients treated with ifosfamide, there have

been at least 7 documented cases of NCSE in ifosfamidetreated patients (Table 1).2,5-8 The definition of NCSE varies, but most authors agree that its diagnosis requires continuous or near-continuous generalized epileptiform discharges along with mental status change for at least 30 to 60 minutes. We present a case of ifosfamide-related NCSE and review the literature. Our case raises the possibility that NCSE may be more common than previously reported following ifosfamide.

Case Report A 60-year-old woman with a 7-month history of high-grade peritoneal spindle cell and epithelioid carcinosarcoma presented with lethargy, weakness, and abdominal distension. She was found to have acute on chronic renal failure, malignant pleural effusions, malignancy-related ascites, and Staphylococcus aureus bacteremia. She was started on vancomycin and was treated with fentanyl and clonazepam for pain and anxiety. Eight days after admission her lethargy improved, and she was alert, oriented, and appropriately conversant. Despite having 1

New York University School of Medicine, New York, NY, USA New York University Langone Medical Center, New York, NY, USA

2

Corresponding Author: Daniel Friedman, Comprehensive Epilepsy Center, New York University Langone Medical Center, 223 East 34th Street, New York, NY 10016, USA. Email: [email protected] Full-color figures are available online at http://eeg.sagepub.com

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Taupin et al Table 1.  Cases of Nonconvulsive Status Epilepticus Following Treatment With Ifosfamide. Patient no. and reference

Gender

Age (Years)

Onset of Central Nervous System Symptomsa

12

Female

55

Day 3

22

Female

53

Day 3

35

Female

27

Day 2

45

Female

57

Day 3

56

Female

57

Day 4

67

Female

71

Day 3

78 Present case

Male Female

22 60

Not reported Day 2

a

Clinical Signs and Symptoms

Electroencephalogram Findings

Lethargy, confusion, mute Slow background and generalized, triphasic sharpwave complexes Lethargy, unresponsive Generalized, high amplitude to verbal commands, sharp-wave complexes echolalia Lethargy; mute or verbal Generalized medium to high perseveration and amplitude spike-and-wave echolalia and sharp and slow-wave complexes, 1.5-2 Hz Confusion, diminished Generalized medium to high verbal response, amplitude spike-and-wave perseveration and and sharp and slow-wave echolalia complexes, 1-1.5 Hz Perseveration, echolalia, Diffuse theta background and bilateral upper extremity posteriorly predominant myoclonus triphasic complexes Unresponsive to verbal Generalized medium to high commands amplitude spike-and-wave and sharp and slow-wave complexes, 1 Hz Lethargy, mute, staring Not reported Lethargy, confusion, Moderate, diffuse background unresponsive to verbal slowing with generalized commands, facial triphasic complexes, 1-2 Hz myoclonus, eyelid flutter

Treatment Diazepam, levetiracetam Diazepam, levetiracetam Diazepam

Diazepam

Diazepam, phenytoin Phenytoin

Lorazepam Methylene blue, thiamine, levetiracetam, midazolam

“Day 1” is the first day of ifosfamide infusion.

previously experienced encephalopathy with visual hallucinations with the agent, she was started on a palliative course of ifosfamide (2500 mg/m2, 24-hour infusion) and mesna (2500 mg/m2, 24 hour-infusion) 15 days following admission. The patient tolerated the first day of ifosfamide infusion (day 1) without complication, but on day 2 she became lethargic and confused; the infusion was stopped. From the evening of day 2 through day 4 her mental status continued to decline; she grimaced only to noxious stimuli but was otherwise nonresponsive. She also developed occasional eyelid fluttering and myoclonic facial movements. On day 4, she was started on methylene blue and high-dose thiamine. Levetiracetam (500 mg, twice per day) was also started for possible seizures. Video and EEG monitoring on day 5 displayed moderate, diffuse background slowing with frequent periods of generalized, periodic, complexes at 1 to 2 Hz, which were often triphasic and maximal frontally, but occasionally more sharply configured with posterior predominance. Often, complexes were followed by 0.5 to 1.0 seconds of diffuse background attenuation (Figure 1). Because of concerns of NCSE, a benzodiazepine trial was started on day 6, using midazolam in incremental doses of 2 mg up to 10 mg. Six hours later, there was a significant improvement in the patient’s mental status: She was awake and alert but was still unable to follow most verbal

commands. Overnight (day 6-7) the EEG displayed lower amplitude triphasic complexes that decreased in frequency from 1 to 2 Hz in the beginning of the night to 0.4 to 0.5 Hz in the morning, then subsided completely (Figure 2). Throughout the next few days she was able to open her eyes and track people in the room. Unfortunately, she expired on day 10 due to respiratory failure associated with end-stage cancer.

Discussion This case of NCSE following ifosfamide administration illustrates the challenges involved in making the diagnosis, as the clinical presentation of ifosfamide-induced metabolic encephalopathy and NCSE bear a great deal of similarity. A review of the 8 documented cases of ifosfamide-induced NCSE demonstrates that confusion, lethargy, and echolalia are the clinical features that most commonly precede or co-occur with an ictal EEG pattern (Table 1). These signs and symptoms do not differ from those reported in cases of ifosfamide-related neurotoxicity that are not classified as NCSE.3 Even the myoclonus observed in the present case, which prompted acquisition of an EEG, has been reported in ifosfamide-treated patients both with and without NCSE.6,9 EEG is therefore essential for a diagnosis of NCSE, yet findings can be subtle. Epileptiform activity must be

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Clinical EEG and Neuroscience 45(3)

Figure 1.  EEG on day 5 displaying diffuse background slowing and generalized, periodic complexes, often with triphasic morphology. Note the diffuse background attenuation following a complex (black arrow).

differentiated from the EEG abnormalities found in up to 65% of ifosfamide-treated patients, which can include the appearance of sharp and triphasic waves.10 In cases of ifosfamideinduced NCSE, EEG findings include generalized periodic epileptiform discharges (GPEDs) with varying morphology: sharp-wave complexes, spike-and-wave, and sharp and slowwave complexes (Table 1). In a subset of NCSE cases, the GPEDs have a triphasic morphology that differs slightly from the classic triphasic waves of metabolic encephalopathy. For example, Wengs et al6 describe an ifosfamide-treated patient with EEG findings of diffuse slowing with superimposed triphasic complexes that were posteriorly predominant with no anterior–posterior lag. In this case, the occasional posterior predominance and diffuse background attenuation following some triphasic complexes were suggestive of an ictal pattern. These findings, in conjunction with the clinical features of eyelid fluttering, myoclonic facial movements, lethargy, and confusion prompted discontinuation of ifosfamide, doses of methylene blue and thiamine for possible metabolic toxicity, and administration with levetiracetam and midazolam for possible NCSE. Although all these medication adjustments may have contributed to the patient’s improvement, the EEG and clinical changes seen shortly after midazolam administration are consistent with a diagnosis of NCSE. If this were a case of metabolic toxicity alone, EEG normalization without clinical improvement would be the expected result following benzodiazepine administration.11 Electroclinical improvement following benzodiazepine administration was also seen in six of the seven reported cases of ifosfamide-induced NCSE, with no clear pattern to the order and timing of the EEG and clinical changes. We have presented a case of NCSE following ifosfamide therapy. The clinical signs and symptoms of NCSE are not significantly different from ifosfamide-induced metabolic encephalopathy, so EEG monitoring is necessary to make the diagnosis and institute appropriate therapy. Since it is unlikely that EEG’s are uniformly obtained, many cases may go unrecognized.

Figure 2.  EEG on day 7 demonstrated diffuse background slowing without evidence of periodic complexes.

Unfortunately, it is unknown whether prophylactic treatment with anticonvulsants can prevent NCSE in patients undergoing ifosfamide treatment. This is a potential area of further research. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Friedman receives salary support from The Epilepsy Study Consortium, a non-profit organization dedicated to improving the lives of epilepsy patients, and devotes 15% of his time to work done for the Consortium. The Consortium receives payments from a large number of pharmaceutical companies for consulting activities. All payments are made to The Consortium and not to Dr. Friedman directly. Since there are so many companies contributing, the amount from each company toward Dr Friedman’s salary is minimal. Within the past year, the Epilepsy Study Consortium received payments from 21 companies. All payments are reported annually and reviewed by New York University’s Conflict of Interest Committee. Dr Friedman receives research support from UCB Inc/Schwarz Pharma and the American Epilepsy Society. Dr Friedman also receives royalties from the sale of What Do I Do Now: Epilepsy (Oxford University Press, 2011) and has been a consultant for GlaxoSmithKline.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Taupin et al 5. Primavera A, Audenino D, Cocito L. Ifosfamide encephalopathy and nonconvulsive status epilepticus. Can J Neurol Sci. 2002;29:180-183. 6. Wengs WJ, Talwar D, Bernard J. Ifosfamide-induced nonconvulsive status epilepticus. Arch Neurol. 1993;50:1104-1105. 7. Bhardwaj A, Badesha PS. Ifosfamide-induced nonconvulsive status epilepticus. Ann Pharmacother. 1995;29:1237-1239. 8. Kaplan PW. Nonconvulsive status epilepticus in the emergency room. Epilepsia. 1996;37:643-650.

9. Savica R, Rabinstein AA, Josephs KA. Ifosfamide associated myoclonus-encephalopathy syndrome. J Neurol. 2011;258:17291731. 10. Meanwell CA, Blake AE, Kelly KA, Honigsberger L, Blackledge G. Prediction of ifosfamide/mesna associated encephalopathy. Eur J Cancer Clin Oncol. 1986;22:815-819. 11. Fountain NB, Waldman WA. Effects of benzodiazepines on triphasic waves: implications for nonconvulsive status epilepticus. J Clin Neurophysiol. 2001;18:345-352.

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Ifosfamide chemotherapy and nonconvulsive status epilepticus: case report and review of the literature.

We present a patient with peritoneal carcinosarcoma who was treated with the alkylating agent ifosfamide and experienced a rapid decline in mental sta...
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