Reversible Posterior Leukoencephalopathy Syndrome Induced by Pazopanib

The reversible posterior leukoencephalopathy syndrome (RPLS) has been reported as a distinct clinical entity by several investigators [1, 2]. It is a clinical/radiological syndrome characterized by headache, seizures, impaired vision, acute hypertension, and typical magnetic resonance imaging findings such as hyperintensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images involving the posterior circulation areas, especially the parietal and occipital lobes which are usually symmetric. The hallmark of RPLS is the almost complete recovery in the majority of the cases of clinical symptoms and brain imaging findings, which usually occurs within days to weeks [3].

The correlation of the syndrome with several conditions like hypertensive encephalopathy, eclampsia, collagen vascular disorders, renal dysfunction, thrombotic thrombocytopenic purpura, acute porphyria, Guillain-Barré syndrome and the usage of immunosuppressive agents (especially calcineurin inhibitors like cyclosporine) is well defined [3]. There are numerous case reports in the literature that depict its occurrence in cancer patients. The list of common anticancer and supportive care drugs that predispose to RPLS is expanding and includes a large number of chemotherapeutic agents such as cisplatin, cyclophosphamide, high-dose corticosteroids, L-asparaginase, and growth supportive factors such as granulocyte colony-stimulating factor (G-CSF), and erythropoietin [4]. In the last few years an increased number of case reports involving new targeted drugs, particularly angiogenesis inhibitors have been reported. Agents such as bevacizumab, sunitinib and sorafenib and other targeted drugs have been implicated in new cases of RPLS [5‐10].

Pazopanib is an oral tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-Kit [11]. After a positive phase III randomized clinical trial in patients with advanced renal cell cancer [12] pazopanib was approved by the US FDA in October 2009 for the treatment of advanced renal cell carcinoma (RCC). The toxicity profile of the drug mimics that of other anti-angiogenesis TKIs consisting mainly of diarrhoea, hypertension, nausea and fatigue but until now no cases of RPLS induced by pazopanib have been reported [13, 14].

The case described above matches both clinical and radiological criteria of RPLS and to the best of our knowledge this is the first case of pazopanib induced RPLS. There are several other neurological complications such as brain metastasis, stroke or, drug-induced delirium which can be clinically confused with RPLS, and therefore, the differential diagnosis of the syndrome is very important; brain MRI is mandatory for the correct diagnosis.

The treatment for RPLS is symptomatic, similar to malignant hypertension, with the goal of lowering diastolic blood pressures to around100 mm Hg within few hours. Even if hypertension is mild, it is still recommended to reduce blood pressure [4]. Whereas treatment with anticonvulsants is the standard of care for seizures associated with the acute phase of RPLS, this does not necessitate longterm antiepileptic treatment [3]. In cases of RPLS induced by anticancer drugs, it is recommended that the offending agent be withdrawn, if possible, and that blood pressure be controlled [4]. In selected cases where there is no alternative treatment, anti-VEGF agents can be re-administered at lower dose with close monitoring of blood pressure [17].

Although the pathogenesis of RPLS is not fully understood there are several mechanisms that could be proposed to explain how the syndrome was triggered by pazopanib in our patient. The administration of pazopanib for mRCC patients has been frequently correlated with hypertension ranging between 40-93% and a significant proportion of them (9-25%) developed severe (grade III) hypertension [12, 18]. Even a modest increase in blood pressure, if it is acute, especially in the presence of an underlying endothelial dysfunction, may exceed protective autoregulatory mechanisms resulting in breakdown of the blood–brain-barrier, pathological vasodilation, capillary leakage which result to extravasation of fluids into the brain parenchyma [19]. The posterior circulation is more vulnerable to those sudden changes of blood pressure due to the relative lack of adrenergic nerves around pial and intracerebral vessels in comparison with the anterior circulation of the brain [20]. Moreover, pazopanib has strong antiangiogenic properties via inhibition of the VEGF and PDGF pathways in vessels cells which suggests that the vascular endothelium may be an important site of toxicity [11].Disrupted or immature vascular endothelium may result in vascular leak and white matter oedema characteristic of RPLS especially in the setting of a sudden increase of the blood pressure like that occurring in our patient.

It is worth mentioning that in a study about the association of RPLS with anticancer drugs [21], a predominance of RPLS cases affecting women, especially those of premenopausal age was reported. There are several genes that are oestrogen-regulated and are actively involved in the vascular physiology like endothelin-1, prostacyclin cyclooxygenase, VEGF and endothelial nitric oxide synthase (eNOS). Our patient was a 40 years old premenopausal woman and oestrogen activation of those genes may also contributed to endothelial toxicity and played a role in the pathogenesis of RPLS [22, 23]. This hypothesis is also fueled by the well established correlation of RPLS and eclampsia.

In conclusion this is the first case of pazopanib induced RPLS. Although usually reversible, RPLS is a serious and potentially life threatening adverse effect, if untreated, that should be considered by physicians treating mRCC patients with pazopanib. As we have entered the era of multiple antiangiogenic targeted agents for the treatment of mRCC more cases of RLPS are anticipated.