Cisplatin-related Cerebral Infarction in Carcinoma of the External Auditory Canal.

BACKGROUND: Despite the known association between cisplatin and vascular toxicity, the mechanism of cisplatin-associated cerebral infarction, a relatively rare complication, remains unclear. We describe an investigation of potential biomarkers that could facilitate the early detection of this complication in a relevant case. CASE DESCRIPTION: A 59-year-old male diagnosed with stage III carcinoma of the external auditory canal underwent cisplatin chemotherapy. Seven days after the last dose, he presented with a disturbance of consciousness due to basilar artery occlusion, which was associated with chemotherapy administration. The patient recovered consciousness after thrombectomy. Interestingly, an increase in serum von Willebrand factor (vWf) activity was observed. The vWf activity level gradually normalized 5 months after cisplatin administration.
CONCLUSIONS: Endothelial injuries could be responsible for cisplatin-associated cerebral infarction. Moreover, a cisplatin-induced cerebral infarction increase in serum vWf activity, which indicates endothelial injury, suggests that this molecule might be a useful biomarker for predicting cisplatin-associated cerebral infarction. Copyright:

Introduction

Chemotherapy-associated cerebral infarction, such as that induced by cisplatin, is rare and poorly understood.[123] Despite its reputation as an effective chemotherapeutic drug, cisplatin has been shown to induce vascular toxicity and be associated with cerebral infarction;[45] however, its mechanism of action remains unknown. Here, we describe a case presenting with cisplatin-associated cerebral infarction.

Case Report

A 59-year-old male was diagnosed with stage III carcinoma of the external auditory canal, with no apparent brain metastases. The patient had no previous medical history of atrial fibrillation, ischemic heart disease, or stroke. After cancer was removed, the patient was treated with cisplatin to prevent cancer recurrence. Seven days after cisplatin administration, he suddenly presented with a disturbance of consciousness. Head magnetic resonance imaging showed basilar artery occlusion, which was associated with chemotherapy administration [Figure 1a]. Once diagnosed, an endovascular stent retrieval thrombectomy was performed [Figure 1b and c]. The patient recovered consciousness after thrombectomy, although there were some ischemic lesions visible on diffusion-weighted images [Figure 1d]. The patient then began taking a direct oral anticoagulant to prevent thrombosis. Serum von Willebrand factor (vWf) activity increased during the occurrence of cerebral infarction. This vWf activity gradually decreased after the cerebral infarction and normalized 5 months after cisplatin administration [Figure 2]. The patient did not experience a recurrence of cerebral infarction after cisplatin administration.

Figure 1

(a) Magnetic resonance angiography shows basilar artery occlusion (b) Preoperative cerebral angiography also shows basilar artery occlusion (black arrow) (c) Postoperative cerebral angiography shows the recanalization of the basilar artery (d) Diffusion-weighted image shows ischemic lesions on the cerebellum and brainstem

Figure 2

Time-course measurement of serum von Willebrand factor activity

Discussion

A previous study reported an incidence rate of 0.137% for chemotherapy-associated ischemic stroke and observed that most of the patients exhibited a latency period of ≤10 days after the latest chemotherapy session.[6] Regarding cisplatin usage specifically, a previous study of 108 patients with non-small cell lung carcinoma who received cisplatin and gemcitabine treatment concluded that chemotherapy is a powerful risk factor for arterial thrombosis, including cerebral infarction.[7] The findings of that and other previous studies are consistent with our findings demonstrating that one patient experienced ischemic stroke combined with the reported occurrence of cerebral infarction.[1456]

The mechanism of chemotherapy-associated cerebral infarction is multifactorial. Cancer-induced hypercoagulation can cause a thrombus. Possible mechanisms, including platelet activation, alteration of the clotting cascade (including hyperfibrinolysis), and disturbances of prostacyclin–thromboxane homeostasis, could explain the 4- to 6-fold increased risk of thrombosis in cancer patients relative to the general population.[8] All patients in the current study exhibited increased D-dimer levels, which can indicate the presence of a thrombus.

Cisplatin-associated vascular toxicity can also increase the risk of stroke. Moore et al. showed that when diagnosing cisplatin-induced cerebral infarction, risk factors for thromboembolism such as atherosclerosis and preexisting cardiovascular diseases can be excluded from consideration.[1] Lajer and Daugaard reported that cisplatin induces hypomagnesemia in 76%–87% of treated patients.[9] Low magnesium levels increase the intracellular calcium concentration, which initiates smooth muscle contraction and causes vasospasm and tissue ischemia. Other possible mechanisms could include cisplatin-associated damage of the endothelium and basement membrane, which could cause a thrombotic effect that leads to ischemic cerebrovascular disease. Nuver et al. showed that human endothelial cells exposed to cisplatin in vitro upregulated the production of inflammatory proteins, which are assumed to initiate vascular inflammation and endothelial dysfunction.[10] Moreover, since vWf is produced by endothelial cells, it is considered to be a suitable biomarker of endothelial cell activation and vascular damage.[11] Physiologically, vWf mediates the mechanisms of endothelial injury repair, which is achieved mainly through the platelet adhesion and aggregation. Furthermore, Uchiyama et al. reported that platelet aggregation is increased in patients with atherothrombotic stroke and transient ischemic attacks, and this event is correlated with an increase in large vWf multimers, defined as those with molecular weights of ≥13–14 × 106 kDa.[12] One noteworthy aspect of the afore-mentioned case study was the increase in serum vWf activity at the onset of cerebral infarction and then normalized within several months, suggesting endothelial injury. The previous reports showed that the vWf level normalized approximately 4 months after endothelial injury.[1113] Taken together, these data suggest that serum vWf can be a useful biomarker for predicting cisplatin-associated cerebral infarction. However, confounding factors such as malignancy and concomitant medication cannot be excluded from the study.

Moreover, cisplatin-associated cerebral infarction is likely suspected in cases, in which this cerebrovascular event occurs shortly after chemotherapy administration. Alternative chemotherapy programs that exclude cisplatin administration may reduce the occurrence of cerebral infarction. One limitation of this study was our inability to measure the serum activity of vWf in all cases. In addition, a comparison of the baseline vWF activity before chemotherapy administration with the posttreatment level would have been ideal. Second, vWf is not specific for cisplatin-induced cerebral infarction because vWf activity may increase in noncancer patients who experienced a stroke. Some animal models have shown that serum vWf activity increased in an ischemic model.[14] Our observations regarding serum vWf activity thus require further analysis. In conclusion, patients who underwent cisplatin-based chemotherapy exhibit an increased risk for the rare complication of cerebral infarction. Moreover, we observed an increase in vWf activity during the onset of cerebral infarction, which was later normalized within several months. Taken together, serum vWf activity could be a potentially useful biomarker for predicting cisplatin-associated cerebrovascular diseases.

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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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.