Reversible Posterior Leukoencephalopathy Syndrome Induced by Sunitinib
Authors: German Martín, Lorena Bellido, Juan Jesus Cruz
Journal: Journal of Clinical Oncology (2007)

TO THE EDITOR: We would like to report the occurrence of reversible posterior leukoencephalopathy that we believe is directly attributable to sunitinib malate (Sutent; Pfizer Pharmaceuticals Group, New York, NY), a receptor tyrosine kinase inhibitor with antiangiogenic activity that is approved for the treatment of advanced renal cell carcinoma. A 70-year-old woman diagnosed with renal cell carcinoma and bone metastasis was first treated with palliative nefrectomy and interferon plus vinblastine. Afterwards, she was enrolled in a phase II clinical trial with sunitinib malate (50 mg daily for 4 weeks every 6 weeks). Two weeks after starting the treatment, she was admitted to the hospital because of partial seizures affecting her left superior extremity, headache, and vision loss in the previous 2 days. The physical examination was normal except for cortical blindness and hypertension (170/100 mmHg). Blood tests, including coagulation study and gasometry, were unremarkable. Computed tomography of the brain showed symmetric subcortical hypodense lesions in the occipital lobes, consistent with reversible posterior leukoencephalopathy syndrome (RPLS). Magnetic resonance imaging was requested to rule out brain micrometastasis and it confirmed the findings of RPLS: symmetric hyperintense T2 signal involving bilateral occipital and parietal lobes in the subcortical distribution (Fig 1). Sunitinib administration was withheld and the patient was treated with anticonvulsants and antihypertensives. She recovered completely, was discharged in a few days and had a normal brain computed tomography performed 1 month later. The RPLS was initially reported by Hinchey et al. It is a clinical condition characterized by headache, seizures, impaired vision, acute hypertension, and typical magnetic resonance imaging and computed tomography imaging findings (symmetric and reversible). This syndrome has been described related to different circumstances: hypertensive encephalopathy, eclampsia, collagen vascular disorders (systemic lupus erythematosus, polyarteritis nodose, Behcet), trombotic thrombocytopenic purpura, acute porphyria, postcarotid endarterectomy, and Guillain-Barre syndrome. However, it is most commonly caused by immunosuppressive agents and cytotoxic drugs as cyclosporine A, tacrolimus, interferon alfa, cisplatin, cytarabine, IV immunoglobulins, L-asparaginase, and more recently by bevacizumab (antiangiogenic agent) and sorafenib (tyrosine kinase inhibitor). Its pathogenesis is not precisely known. It is postulated that the alterations can be related with the appearance of vasogenic edema because of elevation in the blood pressure (vasospasm) or because of toxic damage to blood-brain barrier or vascular endothelium. Sunitinib has a dual activity: extracellular action against vascular endothelial growth factor receptor (antiangiogenic) and intracellular action against tyrosine kinase domains, which can produce hypertension. In our case, the set of symptoms could be caused through both mechanisms.