Journal Mobile Options
Table of Contents
36, No. 1-2, 2013
Issue release date: February 2013
Section title: Case Report · Kasuistik
Onkologie 2013;36:46–48
(DOI:10.1159/000346676)

Acute Stroke Secondary to Carotid Artery Dissection in a Patient with Germ Cell Tumour: Did Cisplatin Play a Role?

Khadjooi K. · Adab N. · Kenton A.
Department of Neurosciences, University Hospitals Coventry and Warwickshire, United Kingdom
email Corresponding Author

Dr Kayvan Khadjooi

Department of Stroke Medicine, Addenbrooke‘s Hospital Box 83

Cambridge University Hospitals NHS Foundation Trust

Hills Road, Cambridge CB2 0QQ, United Kingdom

kayvan@nhs.net


Abstract

Background: Cisplatin-based chemotherapy – mainly the bleomycin, etoposide and cisplatin (BEP) regimen – has significantly improved the prognosis of testicular germ cell tumours (GCT). However, it has serious vascular side effects, including acute ischemic stroke. Case Report: A 37-year-old man with no conventional cerebrovascular risk factors presented with right arm clumsiness followed by a transient episode of expressive dysphasia 3 h later. He was receiving the third cycle of BEP for metastatic retroperitoneal GCT. Brain computed tomography (CT) and diffusion-weighted magnetic resonance imaging (MRI) confirmed multiple acute infarctions in the left middle cerebral artery territory. MR angiography and CT angiography showed a dissection with flaps extending into the left internal and external carotid arteries. The patient was anticoagulated and made an almost complete recovery. Conclusion: Carotid artery dissection has not been reported as the cause of cisplatin-associated stroke in patients with GCT. This case demonstrates the potential for cisplatin-induced mechanisms causing carotid dissection, particularly considering the close temporal association of BEP and the event in our patient. In young patients with excellent curative potential from GCT, every effort should be made to minimise the risk of disabling side effects of BEP. After a stroke, imaging of intracranial and extracranial arteries, monitoring and correction of serum magnesium is recommended. The decision to continue or discontinue cisplatin-based chemotherapy should be individualised.

© 2013 S. Karger AG, Basel


Related Articles for ""

Close Related Articles


Schlüsselwörter

Akuter Schlaganfall

Karotisdissektion

Cisplatin

Keimzelltumor

Zusammenfassung

Hintergrund: Chemotherapie mit Cisplatin, insbesondere das Bleomycin/Etoposid/Cisplatin (BEP)-Regime – hat die Prognose von testikulären Keimzelltumoren signifikant verbessert. Cisplatin hat jedoch ernste vaskuläre Nebenwirkungen, einschließlich des akuten ischämischen Schlaganfalls. Fallbericht: Ein 37-jähriger Mann ohne konventionelle zerebrovaskuläre Risikofaktoren wurde mit Funktionsstörungen im rechten Arm gefolgt von einer vorübergehenden Episode expressiver Dysphasie 3 h später vorstellig. Zu diesem Zeitpunkt erhielt er gerade Zyklus 3 einer BEP-Cemotherapie aufgrund eines metastasierten retroperitonealen Keimzelltumors. Eine computertomographische (CT) Aufnahme des Gehirns und die diffusionsgewichtete Magnetresonanztomographie (MRT) bestätigten multiple akute Infarkte im Bereich der linken mittleren Gehirnarterie. Die MR-Angiographie und CT-Angiographie ergaben eine Dissektion mit in die linke interne und externe Karotis hineinragenden Klappen. Eine Antikoagulationstherapie wurde begonnen, und der Patient erholte sich fast vollständig. Schlussfolgerung: Karotisdissektion ist bisher nicht als eine Ursache des cisplatinassoziierten Schlaganfalls bei Patienten mit Keimzelltumoren berichtet worden. Dieser Fall demonstriert das Potential für cisplatininduzierte Mechanismen, die zu einer Karotisdissektion führen können, insbesondere angesichts des engen zeitlichen Zusammenspiels der BEP-Chemotherapie und des Schlaganfalls bei unserem Patienten. Bei jungen Patienten mit Keimzelltumoren und ausgezeichneten Heilungsaussichten sollte das Risiko behindernder Nebenwirkung der BEP-Chemotherapie soweit wie möglich minimiert werden. Nach einem Schlaganfall ist es empfehlenswert, bildgebende Studien der intrakranialen und extrakranialen Arterien durchzuführen sowie den Serummagnesiumspiegel zu beobachten und zu korrigieren. Die Entscheidung, ob die Cisplatin-Chemotherapie fortgesetzt bzw. abgebrochen werden sollte, muss individuell getroffen werden.

Introduction

Cisplatin is a potent chemotherapeutic agent with a broad spectrum of antineoplastic activity against various types of tumours. Cisplatin-based chemotherapy, most commonly the bleomycin, etoposide and cisplatin (BEP) regimen, has significantly improved the prognosis of testicular germ cell tumours (GCT), the most common solid tumour among young males, with 5-year survival rates exceeding 90% [1]. Although the BEP regimen is usually well tolerated, its toxicity profile is significant [2,3]. Vascular toxicity is a recognised side effect of cisplatin-based chemotherapy. As many as 7.4 to 19% of patients with GCT who receive cisplatin develop acute thromboembolic events during chemotherapy, with the majority being venous complications, in particular pulmonary embolism [2,4]. The incidence of arterial thromboembolic events, such as acute myocardial infarction, acute cerebral infarction, and thrombosis of major arteries such as the aorta [3] or iliac arteries, is 0.3–1.6% [2,5]. The majority of these thromboembolic events happen after a median number of 3 cycles of chemotherapy, although they have been reported even after only 1 cycle [2].

Case Report

A 37-year-old right-handed man presented with sudden onset of right arm clumsiness and numbness. He also had a transient episode of expressive dysphasia 3 h after the start of right monoparesis. His past medical history consisted of a poorly differentiated retroperitoneal GCT, with metastasis to the inferior mediastinal nodes, diagnosed 8 weeks earlier. There was no primary lesion in the testis, and biopsy did not provide a definitive tissue diagnosis despite extensive immunohistochemistry tests; however, given the size of the mass, normal serum alpha-fetoprotein and only mildly elevated beta-human chorionic gonadotropin (24 mIU/ml), he was considered to have seminomatous type GCT with a good prognosis according to the IGCCCG classification. However, given the poorly differentiated nature of the GCT, 4 cycles of BEP chemotherapy were planned. He showed a very good response to chemotherapy, and 2 weeks after the start of BEP beta-human chorionic gonadotropin (hCG) was back to normal, and lactate dehydrogenase (LDH) – which was 1,327 IU/l on day 1 of chemotherapy – decreased considerably.

The neurological symptoms started 1 day before elective admission for completion of the third cycle (for the last dose of bleomycin), and the patient mentioned his neurological symptoms during this admission. There was no recollection of head or neck trauma, neck pain, sudden cough or sneeze. He was a non-smoker with no personal or family history of cerebrovascular disease and no conventional risk factors for stroke. On examination he was in sinus rhythm with a blood pressure of 128/67. He had mild right arm weakness, difficulty with fine movements of the right hand and right-sided visuospatial difficulties with no evidence of Horner’s syndrome or cranial nerve palsies. Brain computed tomography (CT) scan showed multiple areas of low attenuation in the cortex and subcortical white matter of the left cerebral hemisphere with no abnormal enhancement of intravenous contrast. Diffusion-weighted magnetic resonance imaging (MRI) showed acute infarctions in the left middle cerebral artery (MCA) territory, with no evidence of metastasis (fig. 1). The thrombophilia and vasculitis screen was negative but serum magnesium was 0.66 mmol/l (range 0.7–1 mmol/l). Carotid Doppler showed moderate to severe stenosis of the left common carotid artery extending into both internal and external carotid arteries for about 1 cm suggestive of a short dissection with an attached thrombus. MR angiography and CT angiography confirmed a dissection with flaps extending into the left internal and external carotid arteries, explaining the multiple infarcts as thromboembolic phenomenon (fig. 2).

Fig. 1

Diffusion-weighted magnetic resonance imaging (MRI) scan of a 37-year-old man receiving cisplatin-based chemotherapy for retroperitoneal germ cell tumour, who presented with sudden onset of right arm clumsiness and numbness and a transient episode of expressive dysphasia. The scan shows acute infarctions in the left middle cerebral artery (MCA) territory.

http://www.karger.com/WebMaterial/ShowPic/182981

Fig. 2

Computed tomography angiogram of the patient showing left common carotid dissection with flaps extending into the left internal and external carotid arteries.

http://www.karger.com/WebMaterial/ShowPic/182980

The patient was started on anticoagulation with low molecular weight heparin (LMWH) and made a good recovery following a period of rehabilitation. The oncology team decided that while he is on LMWH, it was safe to complete the 4th cycle of BEP. 2 months later, his tumour markers were all normal, and CT scan showed a small residual retroperitoneal mass which continued to regress in the follow-up CT scans. In the 4-months stroke follow-up visit, his modified Rankin scale was 1, and carotid Doppler showed normal flow in the left carotid artery. In the 18-months oncology follow-up visit, he was well with no suspicion of recurrence.

Discussion

Cisplatin-induced vascular toxicity can be acute (during the application of chemotherapy or immediately thereafter) or late (cumulative) [2]. Cisplatin is believed to initiate degenerative processes of vessel walls in all types of arteries and increase the risk of thromboembolic events, leading to stroke and acute myocardial infarction. [2,3,5]. The pathophysiologic basis of this vascular toxicity is not fully understood, and several mechanisms have been proposed: acute effects on vascular endothelium leading to endovascular damage and dysfunction, hypomagnesaemia, vasospasm, abnormalities in the coagulation cascade directly produced or induced by chemotherapy such as platelet aggregation or elevated plasma von Willebrand factor levels [6,7].

Carotid artery dissection has not been reported as the cause of cisplatin-associated stroke among male patients with GCTs, and an overview of 10 reported stroke cases by Etgen et al. [5] does not mention dissection as an etiologic factor.

In a study of 105 patients with advanced head and neck cancer treated with selective high-dose tumour-directed intraarterial cisplatin using a transfemoral approach for selective catheterisation of the relevant artery, Gemmete [8] reported 2 asymptomatic distal common carotid artery dissections that were considered as catheter-related complications. Ghosh et al. [9] described a 36-year-old man with myocardial ischemia secondary to chronic spontaneous coronary artery dissection that had its onset during a course of cisplatin-based chemotherapy for testicular cancer 12 years earlier.

We hypothesise that cisplatin may have contributed to the carotid artery dissection in our case. Although carotid dissection can happen without trauma in a young patient, the close temporal association of chemotherapy and dissection in our patient is supportive of a causal link, especially considering that most of the ischemic strokes in other reported cases developed within the first days after chemotherapy [5].

Presence of low plasma magnesium in our patient is another supportive factor. A large number of patients receiving cisplatin develop hypomagnesaemia which increases the sensitivity of arterial smooth muscle cells leading to vasospasm [5,7], and there is some evidence that impaired endothelium-dependent vasodilatation that is not the result of stroke can predispose to carotid artery dissection [10]. It has been suggested that damage to the arterial wall layers through proteolytic, oxidative, or autoimmune mechanisms in inflammatory or infective processes may lead to carotid artery dissection [10]. Cisplatin can directly injure the endothelium and also reduce endothelial cell migration, an essential process for vascular remodelling and regeneration in several physiological and pathological situations, potentially predisposing to dissection [11].

Conclusion

This case demonstrates the potential for cisplatin-induced mechanisms causing carotid artery dissection in patients with GCTs. Clearly, more evidence is needed to establish this relationship. In these young patients – who have an excellent curative potential from their cancer – every effort should be made to minimise the risk of disabling side effects of cisplatin-based chemotherapy. After a stroke, extensive vascular investigations should be initiated, including appropriate imaging of the intracranial and extracranial arteries to look for evidence of dissection. Monitoring of serum magnesium and correction of hypomagnesaemia is recommended. Following a vascular event, the decision to continue or discontinue cisplatin-based chemotherapy should be individualised. Some authorities recommend discontinuation of cisplatin [6] and using alternative systemic treatment regimens or radiotherapy. Some patients may be advised to remain on cisplatin-based chemotherapy accompanied by anticoagulation, such as our patient.

Disclosure Statement

The authors declare no conflict of interests.


References

  1. Evans C, Williams M, Mazhar D: Long-term cardiovascular risk following platinum-based chemotherapy for germ cell tumors. Future Oncology 2010;6:365–8.
  2. Dieckmann KP, Gerl A, Witt J, Hartmann JT; German Testicular Cancer Study Group: Myocardial infarction and other major vascular events during chemotherapy for testicular cancer. Ann Oncol 2010;21:1607–11.
  3. Dieckmann K, Gehrckens R: Thrombosis of abdominal aorta during cisplatin-based chemotherapy of testicular seminoma. BMC Cancer 2009; 9:459.
  4. Weijl N, Rutten M, Zwinderman A, Keizer H, Nooy M, Rosendaal F, Cleton F, Osanto S: Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature. J Clin Oncol 2000;18:2169–78.

    External Resources

  5. Etgen T, Weidenhöfer G, Kubin T: Cisplatin-associated occlusion of the internal carotid artery. Onkologie 2009;32:754–7.
  6. Martín GG, Fernández SP, Castro VS, Cueto OH, Acebal MR: Vertebral artery occlusion after chemotherapy. Stroke 2008;39:e38.
  7. Meattini I, Scotti V, Pescini F, Livi L, Sulprizio S, Palumbo V, Sarti C, Biti G: Ischemic stroke during cisplatin-based chemotherapy for testicular germ cell tumor: case report and review of the literature. J Chemother 2010;22:134–6.

    External Resources

  8. Gemmete JJ: Complications associated with selective high-dose intraarterial cisplatin and concomitant radiation therapy for advanced head and neck cancer. J Vasc_ Interv Radiol 2003;14:743–8.
  9. Ghosh N, Chow C, Korley V, Chisholm R: An unusual case of chronic coronary artery dissection: did cisplatin play a role? Can J Cardiol 2008;24: 795–7.
  10. Thanvi B, Munshi SK, Dawson SL, Robinson TG: Carotid and vertebral artery dissection syndromes. Postgrad Med J 2005;81:383–8.
  11. Montiel M, Urso L, de la Blanca EP, Marsigliante S, Jiménez E: Cisplatin reduces endothelial cell migration via regulation of type 2-matrix metallo-proteinase activity. Cell Physiol Biochem 2009;23: 441–8.

Author Contacts

Dr Kayvan Khadjooi

Department of Stroke Medicine, Addenbrooke‘s Hospital Box 83

Cambridge University Hospitals NHS Foundation Trust

Hills Road, Cambridge CB2 0QQ, United Kingdom

kayvan@nhs.net


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Evans C, Williams M, Mazhar D: Long-term cardiovascular risk following platinum-based chemotherapy for germ cell tumors. Future Oncology 2010;6:365–8.
  2. Dieckmann KP, Gerl A, Witt J, Hartmann JT; German Testicular Cancer Study Group: Myocardial infarction and other major vascular events during chemotherapy for testicular cancer. Ann Oncol 2010;21:1607–11.
  3. Dieckmann K, Gehrckens R: Thrombosis of abdominal aorta during cisplatin-based chemotherapy of testicular seminoma. BMC Cancer 2009; 9:459.
  4. Weijl N, Rutten M, Zwinderman A, Keizer H, Nooy M, Rosendaal F, Cleton F, Osanto S: Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature. J Clin Oncol 2000;18:2169–78.

    External Resources

  5. Etgen T, Weidenhöfer G, Kubin T: Cisplatin-associated occlusion of the internal carotid artery. Onkologie 2009;32:754–7.
  6. Martín GG, Fernández SP, Castro VS, Cueto OH, Acebal MR: Vertebral artery occlusion after chemotherapy. Stroke 2008;39:e38.
  7. Meattini I, Scotti V, Pescini F, Livi L, Sulprizio S, Palumbo V, Sarti C, Biti G: Ischemic stroke during cisplatin-based chemotherapy for testicular germ cell tumor: case report and review of the literature. J Chemother 2010;22:134–6.

    External Resources

  8. Gemmete JJ: Complications associated with selective high-dose intraarterial cisplatin and concomitant radiation therapy for advanced head and neck cancer. J Vasc_ Interv Radiol 2003;14:743–8.
  9. Ghosh N, Chow C, Korley V, Chisholm R: An unusual case of chronic coronary artery dissection: did cisplatin play a role? Can J Cardiol 2008;24: 795–7.
  10. Thanvi B, Munshi SK, Dawson SL, Robinson TG: Carotid and vertebral artery dissection syndromes. Postgrad Med J 2005;81:383–8.
  11. Montiel M, Urso L, de la Blanca EP, Marsigliante S, Jiménez E: Cisplatin reduces endothelial cell migration via regulation of type 2-matrix metallo-proteinase activity. Cell Physiol Biochem 2009;23: 441–8.