1. Introduction

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a clinical condition characterized by headaches, seizures, impaired vision, acute hypertension and characteristic neuroimaging findings, especially posterior cerebral white matter edema [1]. It was initially described as a syndrome in 1996 and since then this clinical entity has been increasingly reported in the literature. Nevertheless, the lack of specific diagnostic criteria makes the identification of the syndrome a clinical challenge. Moreover, in the literature RPLS and Posterior reversible encephalopathy syndrome (PRES) are used interchangeably, highlighting the lack of consensus in the description of this clinical entity.

RPLS has been related with a variety of clinical conditions including malignancy and antineoplastic agents (Table 1) [1-13] . Herein we present a case of RPLS in a patient with gastric cancer treated with combination of chemotherapy and Trastuzumab. A comprehensive review of the literature in the relation of RPLS and chemotherapeutic agents in solid tumors is further performed.

Table 1: Medical conditions associated with reversible posterior leukoencephalopathy syndrome.

2. Case Report

We report a case of a 58 year old woman, initially treated with partial gastrectomy (Billroth II) and adjuvant chemoradiotherapy [14] for a for a poorly differentiated, intestinal type gastric adenocarcinoma stage IIIA (pT₂Ν₃M₀). Ten months after treatment completion the patient relapsed both locally and systemically with bilateral lung metastases. Immunohistochemistry confirmed Her 2 positive (3+) staining and the patient started on first line chemotherapy with modified DCF regime (Docetaxel 40 mg/m² on day 1, Cisplatin 40 mg/m2 on day 1 and 5FU 400 mg/m² bolus on day 1 and followed by 1000 mg/m² continuous infusion over 24 hours daily on days 1 and 2, repeated every 14 days) in combination with trastuzumab (6 mg/kg body weight as loading dose on day 1 and after 4 mg/kg body weight on day 1 repeated every 14 days). On day ten post cycle two, she presented at the Emergency Department of our Hospital with tonic-clonic epileptic seizures and throbbing headache. The physical examination was unremarkable while the neurological examination did not reveal any focal deficit. The main clinical and laboratory findings were normal, besides an elevated blood pressure of 177/94 mmHg and respiratory alkalosis from the arterial blood gas. MRI of the brain followed which revealed bilateral subcortical oedema at the occipital and parietal lobes (Figure 1). There were no signs of brain metastases, hemorrhage, or vascular infarction. Lumbar puncture was performed to exclude leptomeningeal disease and/or infection. The cerebrospinal fluid examination was normal (normal physical characteristics, no cancer cells present, normal biochemistry, negative microscopic examination tests for HSV1, HSV2, CMV and EBV). The clinico-radiographic diagnosis was consistent with RPLS. Patient was treated symptomatically with gradual improvement of her mental status, without any residual deficit. Brain MRI performed 4 weeks after this episode revealed that the subcortical edema had resolved (Figure 2). The patient decided against any further chemotherapy and she was offered palliative care support.

Figure 1: Magnetic resonance images of the brain showing diffuse lessions of abnormal magnetic signal mainly in subcortical white matter and in both cerebral hemispheres.

Figure 2: Follow up MRI of brain 4 weeks later showing complete response of pathological lesions.

3. Methods

We searched MEDLINE for papers using the following key words: “reversible posterior leucoencephalopathy syndrome”, “posterior reversible encephalopathy syndrome”, “cancer”, “malignancy”, and “chemotherapy”. Reference lists in the retrieved papers were checked to identify any other published data. Cases were included if there was both clinical and radiological evidence of RPLS, related to chemotherapeutic agents used to treat solid tumors. Only papers written in English language and cases with patients older than 16 years were included in the analysis. Data about the primary tumor, the chemotherapeutic agents used and the intention of the treatment, the age, gender, presenting symptoms and the number of cycles given before the development of the symptoms as well as the clinical and radiologic outcome were analyzed.

To find out if there is any correlation regarding differences between the two independent groups (males vs. females) and blood pressure in patients presented with RPLS we used Mann–Whitney test to compare them. Inferences were made at the 0.05 level of significance with no correction for multiple comparisons.

4. Results

Table 2 [3, 4, 15-67] summarizes the 67 cases, including ours, that were identified in the literature review for patients experiencing symptoms of RPLS when they were exposed to chemotherapy drugs with or without the combination of monoclonal antibodies (bevacizumab [17, 18, 22, 25, 27, 28, 37-39, 46, 51, 52, 55, 56, 58, 59, 63], trastuzumab [45, 65] or zib-aflibercept [60]) or Tyrosine Kinase Inhibitors (pazopanib [63] or erlotinib [4]). Table 3 depicts the drugs that are commonly related with the syndrome. Of the 57 cases where the treatment intention could be assessed, 46 patients (81%) were treated with palliative chemotherapy [4, 15, 17, 18, 20-25, 27-38, 41-46, 49, 51-53, 55-62, 64, 66], 9 patients had adjuvant chemotherapy [16, 19, 26, 39, 40, 47, 48, 54, 65], one neoadjuvant [67] and one treated with curative intent for testicular cancer [50]. Colorectal adenocarcinoma was the most frequent tumor type (n=19) [17, 18, 20, 22, 25, 28, 29, 37, 39, 43, 53, 54, 57-59, 61, 63, 64], followed by lung cancer (n=14; 11 NSCLC [15, 23, 24, 48, 51, 56, 60, 63, 67], 3 SCLC [31, 47, 66]), breast (n=5) [27, 44, 49, 52, 65], pancreatic (n=5) [4, 35, 40, 51, 63], urothelial bladder cancer (n=3) [21, 36, 41], sarcomas (n=3) [3, 42, 63], ovarian (n=4; 2 adenocarcinomas [54, 63] and 2 germ cell tumor (GCT) [16, 19]), gastric cancer (n=3) [34, 45], melanoma (n=2) [62, 63], glioblastoma (n=1) [38], fallopian tube (n=1) [26], cervical (1) [33], intraperitoneal mesothelioma (n=1) [30], cholangiocarcinma (n=1) [46], gall bladder (n=1) [32] and non-seminomatous GCT (n=1) [50].

In 37 cases, chemotherapeutic agents were used alone while in the rest 29 cases they were combined with targeted agents, mainly bevacizumab (Table 3). Gemcitabine was the most common agent as a single drug to cause RPLS. Platinum compounds were the most common drugs to be related with RPLS (26/37 cases), especially cisplatin (14/37). Gemcitabine was the second most common drug (12 cases) but in 7 cases it was combined with a platinum agent. In the majority of the cases (67.8%) the syndrome did appear in the first 3 cycles and in almost half of the cases (49%) in the first 2 cycles of treatment. There was a wide range though when the syndrome could present, varying between 1 and 14 cycles.

Table 2: Patients with RPLS after chemotherapy. BP: Blood Pressure; M: Male; cl: clinical response, N/A: Not assessed; MRI: Magnetic Resonance Imaging, CR: complete response, GCT: Germ Cell tumor; PVB: cisplatin, vinblastine, bleomycin; d: days; w: weeks; F: female; CRC: colorectal cancer, FOLFOX: 5-fluorouracil, leucovorin, Oxaliplatin, FOLFIRI: 5-fluorouracil, leucovorin, Irinotecan; PR: partial response; XELOX capecitabine, oxaliplatin; NSCLC: non small cell lung cancer; SCLC: small cell lung cancer; NSGCT: Non seminomatous germ cell tumor; BEP: bleomycin, etoposide, cisplatin; TCH – Docetaxel, Carboplatin, Trastuzumab.

Table 3: Chemotherapy drugs related with RPLS.

There was a significant prevalence of female patients presenting with the syndrome (Table 4). Indeed, 83% of the cases were women with median age of 53.3 years (range 17-74 years) while the median age of the 11 men was 58.8 years (range 23-81). In the majority of the cases patients presented with elevated blood pressure (BP). Systolic pressure higher than 140 mmHg and/or diastolic pressure higher than 90 mmHg was regarded as hypertension [68]. 44 of the 51 patients (86.3%) with recorded BP, presented with elevated BP. The mean systolic BP was 166.9 mmHg and the mean diastolic was 96.8 mmHg. There was no difference in BP between males and females (Table 4).

Table 4: Clinical characteristics of patients presented with RPLS. †P <0.05 for gender difference with binomial test assuming 50% were women. ‡ No mean age difference between men and women (P = 0.314) (Mann–Whitney test). §No difference in systolic blood pressure between men and women (P = 0.225) (Mann–Whitney test). ¶No difference in diastolic blood pressure between men and women (P = 0.384) (Mann–Whitney test.).

The presenting symptoms and the frequency of RPLS are summarized in Table 5. Although in the majority of the cases the symptoms improved after conservative management, 2 patients unfortunately died in 2 [43] and 3 [61] days after initial admission while three more patients were reported to die in a matter of few days to weeks post presentation due to general deterioration and disease progression [4, 20, 21]. In 23 case (63.9%) of the cases symptoms resolved completely in average of 6.5 days while in 36.1 % of the cases the symptoms partially resolved in 6.4 days. The radiologic resolution of the symptoms was assessed in 40 cases. In 23 cases (57.5%) there was complete resolution in MRI in 4.2 weeks, while in the rest 17 patients (42.5%) the MRI findings partially regressed in 2.6 weeks.

Table 5: Presenting Symptoms of RPLS.

5. Discussion

RPLS is an increasingly recognized clinical syndrome related with a variety of clinical conditions and medications (Table 1). The pathophysiologic mechanisms underlying the syndrome are poorly understood, but it appears to be related to disordered cerebral autoregulation and endothelial dysfunction leading to the characteristic cerebral oedema seen in T2-weighed MRI imaging [1, 69] . This also explains the observation that platinum based chemotherapy with or without antiangiogenic agents are frequently related with RPLS (Table 2). It is well known that platinum agents damage vascular endothelial cells, which can lead to abnormal fluctuations in blood pressure and disrupt the blood brain barrier and axonal swelling [50, 70].

To our knowledge this is the first report where RPLS is related with the combination of DCF and Trastuzumab. Nevertheless, the combination of Trastuzuamb with chemotherapy has been previously reported to cause the syndrome [45, 65]. It is difficult to assess with certainty if the monoclonal antibody itself, the chemotherapeutic agents or the combination have precipitated the event. Trastuzumab blocks tumor angiogenesis by decreasing the production of VEGF and activating antiangiogenic factors, while it can also increase the blood pressure [71]. Besides cisplatin, 5-fluorouracil has been also linked to RPLS either alone [54] or in combination with other agents [17, 18, 28, 45]. Finally, docetaxel has also been related with RPLS when it was combined with Trastuzumab and a platinum compound as in our case [65].

Our case presented with symptoms matching two of the most common clinical findings for RPLS, seizures and headache (Table 5). The brain MRI revealed the characteristic white matter oedema of the occipital and parietal lobes. Even though RPLS was high in the list of differential diagnosis, we tried to rule out other medical conditions like a stroke, demyelinating disorders, encephalitis, leptomeningeal metastases which may have similar presentation [72, 73]. Neuroimaging with MRI is crucial for the diagnosis of RPLS and lumbar puncture can be helpful to exclude any other possible causes.

The role of bevacizumab and novel targeted ant-cancer agents in the development of RPLS have been reviewed recently [5, 74]. Our scope was to review the literature considering the chemotherapy agents that seem to be related with the syndrome. To our knowledge this is the most comprehensive review including cases with solid tumors treated with chemotherapy and developed RPLS. RPLS is characterized by the combination of typical clinical symptoms (Table 5) and the characteristic neuroimaging findings. Cases where the clinical picture was quite typical for the syndrome but the CT or MRI findings were missing, were not included in the analysis [75, 76]. Another case where leucoencephalopathy was evidenced 2 months after the initial symptoms was also excluded [77]. Nevertheless, this raises the question if the lack of MRI confirmation is related to a completely different clinical entity where the findings are not expected to occur, a variant of RLPS where the brain changes may happen sometime after the clinical presentation or the need of more sensitive methods to better characterize the neuronal changes, like proton MR spectroscopy [9] and magnetic resonance angiography [78] .

In 24 cases both CT scan and MRI were used during the initial investigation. In 58% of the cases the CT scan was normal which obviously highlights that MRI should be the diagnostic imaging of choice. Nevertheless, this rate is much higher than the one observed by Singer et al. (37%) [79], and needs to be interpreted cautiously. It is well known though that MRI has higher-resolution capacity, and it has the ability to show small, focal abnormalities that cannot be seen on CT [1, 80]. It seems that a variety of antineoplastic agents have been implicated in the syndrome (Table 3). Although in the majority of the cases the medications have been administered intravenously it was interesting to find that intra-arterial [3], intraperitoneal [26] or hepatic transarterial chemoemblisation could also cause the syndrome [44, 62]. Platinum compounds, especially cisplatin, and gemcitabine, through the increased prothrombotic effect and endothelial dysfunction, were the most frequently encountered agents related with RPLS [81]. The fact that 70% of the cases presented the symptom in the initial period of the treatment may indicate that there is an inherent susceptibility of these patients to develop the syndrome.

The female prevalence of the syndrome has been observed in a previous review [82] as well as in a single institution cohort [79]. Although the exact mechanism underlying this observation is not clear, we can assume that estrogens may play a role. Estrogens have been implicated with endothelial dysfunction [83, 84] and can affect many vascular mediators, like endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), transforming growth factor β (TGF-β), cyclooxygenases [83] regulating the vascular tone [85]. Nevertheless, the interplay between the offending anti-neoplastic agent, estrogens and endothelium in the development of the syndrome needs to be elucidated.

The treatment for RPLS must be symptomatic. Control of blood pressure is important especially for the patients who present with hypertension is commonly encountered with RPLS and in this review 86% of the cases had elevated BP during admission. Nevertheless it is increasingly noticed that normotensive patients may also present with the syndrome [30, 31, 39, 47, 54, 59, 77]. Treatment with anti-epileptics should be initiated in patients with seizures but there is no clear guideline about the overall duration of treatment. This need to be decided on individual basis and it is unlikely that long term antiepileptic treatment will be needed.

Withdrawal of the offending agent seems to fully or partially reverse the symptom or and the neuroimaging findings within a period of few days or weeks, respectively. In the majority of the cases there was no rechallenge of the patients with the same agent. In the few cases where the agent were reintroduced, including bevacizumab [38], no further RPLS-related symptoms were observed [38, 50, 66]. Nevertheless, when another patient was re-exposed to bevacizumab after the initial improvement of the symptoms, he experienced again similar symptoms and the drug was permanently discontinued [58]. In Singer et al. study, 7 out of the 17 patients (41%) that were rechallenged with the same anti-neoplastic treatment did not present the syndrome [79]. None of them though had bevacizumab rechallenge while this was a combined population involving patients with hematologic and solid malignancies. In general though, there is hesitance to carry on with the treatment with the offending agent unless there is strong clinical indication [50].

6. Conclusion

RPLS is a rare syndrome which is increasingly reported in the literature. The combination of the clinical symptoms and characteristic neuroimaging findings can help in the prompt diagnosis and management of this clinical entity. Clinicians need to have a high index of suspicion and request brain MRI when the syndrome is suspected.

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