Journal of Clinical Neuroscience xxx (2017) xxx–xxx

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Journal of Clinical Neuroscience
journal homepage: www.elsevier.com/locate/jocn

Case report

Posterior reversible encephalopathy syndrome (PRES) with
sub-arachnoid haemorrhage after bevacizumab and 5-FU
Jennifer Massey ⇑
Department of Neurology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2006, Australia

a r t i c l e

i n f o

Article history:
Received 17 October 2016
Accepted 22 January 2017
Available online xxxx
Keywords:
PRES
Hypertension
Bevacizumab
Seizures

a b s t r a c t
PRES is a neurological syndrome characterised by reversible subcortical vasogenic brain oedema in
patients with acute neurological signs and symptoms. It occurs in the context of fluctuations in blood
pressure, renal failure, autoimmune disorders, eclamptic syndromes and with use of cytotoxic drugs.
We present the case of a 60 year old female with advanced bowel cancer who was admitted with seizures
and sub-arachnoid haemorrhage, with radiographic features of PRES, shortly after receiving bevacizumab
(Avastin), a VEGF-inhibitor.
Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.

1. Background
First described in 1996; [1] PRES is a neurologic syndrome qualified by well-defined clinical features and characteristic radiologic
imaging. Clinical symptoms and signs in order of prevalence
include encephalopathy, seizure, headache, visual disturbance,
focal neurological deficit and status epilepticus [2]. Associations
between PRES and bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody have been reported since 2006 [3,4].
With increasing prevalence of the cytotoxic medication, numerous
reports of bevacizumab associated PRES have emerged. There are
approximately 40 cases currently reported in the literature,
although reports of bevacizumab induced sub arachnoid haemorrhage in the context of PRES remain rare.

2. Case report
A 60 year old woman, diagnosed with metastatic bowel cancer,
presented with generalised tonic clonic seizures and encephalopathy. This occurred 2 weeks subsequent to the patients 3th dose of
bevacizumab and 5-FU as second line therapy for the malignancy.
The neurologic examination was normal apart from altered mental
status. The patient was normotensive through the majority admission with occasional readings of 140–150 mmHg systolic; however
had been hypertensive above 180 mmHg systolic frequently in the
fortnight prior to presentation, as recorded by her general practi⇑ Fax: +61 2 94631734.
E-mail address: jennifer.massey@hotmail.com

tioner and treating oncologist. Laboratory investigations were
within normal limits. Non-contrast CT scan revealed three areas
of sulcal subarachnoid haemorrhage; and CT angiogram did not
show any underlying vascular abnormality. MRI of the brain performed 48 h after admission showed patchy T2 hyperintense
lesions in the subcortical white matter of the left posterior lobe
(Fig. 1). The MRA revealed irregularities of the intimal aspect of
the M1 segment bilaterally as well as changes consistent with
vasospasm in the left posterior cerebral artery (Fig. 2).
The patient was diagnosed with PRES. Seizures settled with
intra-muscular benzodiazepines. Oral levetiracetam was commenced for further seizure prophylaxis. Although the patient had
received two chemotherapeutic agents in the month prior to presentation, based on frequency of bevacizumab induced PRES in
the literature this was the presumed offending agent. Given the
advanced stage of the patients disease, her ongoing difficulties
with chronic pain and failure of first and second line cytotoxic
agents (oxaliplatin intolerance in the context of peripheral sensory
neuropathy); the patient elected to cease further chemotherapy
and adopt a palliative approach to management.

3. Discussion
Whilst both bevacizumab and 5-FU have been associated with
PRES, the anti-angiogenic effects of bevacizumab and its frequent
association with hypertension make it the most likely offending
agent inducing PRES in this case. Whilst the pathophysiology of
PRES continues to be debated, a leading theory of the underlying
mechanism relates to rapid development of hypertension that

http://dx.doi.org/10.1016/j.jocn.2017.01.005
0967-5868/Crown Copyright Ó 2017 Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Massey J. Posterior reversible encephalopathy syndrome (PRES) with sub-arachnoid haemorrhage after bevacizumab and
5-FU. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.01.005

2

Case report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx

Fig. 1. T2 weighted sequence demonstrating hyperintense lesions in the subcortical
white matter of the left posterior lobe.

Fig. 2. MR angiogram demonstrating irregularities of the intimal aspect of the M1
segment bilaterally and in the left posterior cerebral artery.

exceeds the limits of cerebral hyperperfusion. When the vascular
autoregulatory response fails to accommodate to the patients systemic blood pressure rise, hyperperfusion occurs, damaging the
blood brain barrier and allowing interstitial extravasation of
plasma and macromolecules [2]. The other proposed mechanism
for PRES, which may occur synergistically describes toxic substances including chemotherapeutics causing direct transient
injury to the blood brain barrier by damaging the vascular
endothelium, resulting in arterial microthrombosis, arterial occlusion and cerebral hypoxia/vasogenic oedema [5]. Classically PRES
has been associated with the use of immunosuppressive,
immunomodulatory and chemotherapeutic drugs, as well as intravenous contrast exposure, and illicit stimulant medication triggering hypertensive crises.

Intracranial haemorrhage is common, complicating 10–25% of
cases [6–9]. Sulcal subarachnoid haemorrhage represents the second most common form of bleeding, and is reported as the isolated
type of haemorrhage in 3–8% of cases [2]. Rates of over 80% of
patients with PRES have imaging changes on CTA or MRA consistent with focal or diffuse vasoconstriction or pruning of distal
intracranial arteries, particularly the posterior cerebral arteries.
PRES has been seen in 17–38% of patients with a diagnosis of reversible cerebral vasoconstriction syndrome [10–12].
The mainstay of treatment is cessation of the offending cytotoxic agent and blood pressure control. Although there are no randomised trials of specific blood pressure agents in PRES, the goal is
to reduce blood pressure by 25% in the first few hours, avoid large
fluctuations in blood pressure and avoid excessive blood pressure
reduction [2]. Anecdotal use supports the role of calcium channel
blockers. Seizures are thought to occur both in response to areas
of haemorrhage and secondary to the alterations in parenchymal
macromolecules and regions of interstitial oedema. Generalized
tonic clonic seizures occur in 60–75% of patients [13–15]. Treatment of seizures is with anti-epileptic drugs (AED), as would be
used in any other condition, with no specific guidelines for certain
AEDs. Encephalopathy is a defining feature of the syndrome, seen
in majority of patients in varying severity from mild confusion to
stupor and coma. Confounding factors include seizures, the postictal state and visual changes.
Since 2006 there have been increasing reports of bevacizumab
associated PRES and hypertension is well reported to be the most
common adverse reaction to bevacizumab treatment. Bevacizumab may cause hypertension either due to the rapid rises it
causes in blood pressure resulting in dysregulation of cerebral vasculature, or via endothelial impairment as described above. In our
case, significant hypertension had been recorded in the fortnight
prior to presentation. The typical time to PRES onset post bevacizumab use is within its half life of 20 days [16,17] classically
between 16 h and 11 days from last dose [5]. A higher burden of
PRES has been reported with bevacizumab use in conjunction with
other chemotherapeutics [17]. 5-FU has also been reported to
cause leukoencephalopathy, however this is classically a multifocal, inflammatory variant occurring 6 weeks to 6 months post
treatment [5]. No leukoencephalopathies have been reported with
oxaliplatin to date.
Despite the reversibility of the syndrome, PRES is a potentially
life threatening condition and its association with bevacizumab
should be recognised by physicians prescribing the drug and
managing patients presenting with the above complications. There
have been reports of the syndrome in normotensive patients [18]
and this should broaden physician’s consideration of this diagnosis
in the appropriate clinical setting. When promptly recognised the
syndrome has a good prognosis. Most reports advise indefinite
cessation of bevacizumab [19], post PRES, but the drug remains
an important biologic agent in the use of many metastatic malignancy treatment protocols. Given the medication is currently only
licensed in metastatic disease however, careful monitoring of
hypertension and proteinuria should continue to be performed
routinely due to the obvious risks in a palliative population. No
predictive factors of PRES have been clearly identified to date
[19]. Several studies report PRES following the use of other antiangiogenics including sunitinib as well as other monoclonal antibodies including anti-tumour necrosis factor inhibitors such as
infliximab [20,21].
In conclusion, this case highlights the association of
bevacizumab with PRES and sub-arachnoid haemorrhage. Consideration of PRES as a differential diagnosis should be prevalent
amongst physicians seeing patients with headache, confusion or
visual disturbances during or shortly after bevacizumab treatment,
particularly in patients with new onset hypertension. Prompt

Please cite this article in press as: Massey J. Posterior reversible encephalopathy syndrome (PRES) with sub-arachnoid haemorrhage after bevacizumab and
5-FU. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.01.005

Case report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx

withdrawal of the drug, treatment of blood pressure and management of associated complications increases chances of favourable
outcomes.
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Please cite this article in press as: Massey J. Posterior reversible encephalopathy syndrome (PRES) with sub-arachnoid haemorrhage after bevacizumab and
5-FU. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.01.005