OBSERVATION

Reversible Posterior Leukoencephalopathy Syndrome
After Bevacizumab/FOLFIRI Regimen
for Metastatic Colon Cancer
Jeffrey A. Allen, MD; Ashish Adlakha, MD; Peter R. Bergethon, MD

Objective: To describe a patient with reversible posterior leukoencephalopathy syndrome following the administration of bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor.

with reversible posterior leukoencephalopathy syndrome was found following the administration of irinotecan hydrochloride, leucovorin calcium, and fluorouracil (FOLFIRI) regimen chemotherapy and bevacizumab.

Design: Case report/literature review.

stage IV rectal carcinoma.

Conclusions: Reversible posterior leukoencephalopathy syndrome following treatment with angiogenesis
modulators can occur. In addition to raising clinical suspicion in appropriate patients, this report may yield clues
to the pathophysiologic underpinnings of reversible posterior leukoencephalopathy syndrome.

Results: Clinical and radiographic evidence consistent

Arch Neurol. 2006;63:1475-1478

Setting: University hospital.
Patient: A 52-year-old man receiving chemotherapy for

R

Author Affiliations:
Department of Neurology,
Tufts–New England Medical
Center, Boston, Mass.
Dr Bergethon is now with the
Department of Anatomy and
Neurobiology, Boston
University School of Medicine,
Boston.

EVERSIBLE POSTERIOR LEUKO-

encephalopathy syndrome
(RPLS) is a clinicoradiologic syndrome characterized by headache, confusion, visual disturbance, and seizures
accompanied by subcortical edema, predominantly involving the parietal and occipital lobes.1 Imaging abnormalities often
demonstrate marked improvement after the
initiation of appropriate therapy. Causes of
RPLS include hypertensive encephalopathy, renal failure, eclampsia, and immunosuppressive and cytotoxic medications. Potential pathogenic mechanisms of RPLS have
been proposed, but a unifying mechanism
connecting the causes remains elusive.
We describe a patient with RPLS who
presented 2 weeks after the infusion of irinotecan hydrochloride, leucovorin calcium,
and fluorouracil (FOLFIRI)/bevacizumab
(Avastin) regimen chemotherapy, suggesting a link between RPLS and bevacizumab,
a compound that specifically blocks the actions of vascular endothelial growth factor
(VEGF).
REPORT OF A CASE

A 52-year-old man with stage IV rectal carcinoma with neuroendocrine differentia-

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1475

tion on liver biopsy recently completed an
8-cycle course of cisplatin, 60 mg/m2, and
etoposide phosphate, 120 mg/m2, over a
6-month period. Five weeks after cisplatin and etoposide therapy, cycle 1 of the
FOLFIRI regimen and bevacizumab was
initiated. Dosing consisted of irinotecan,
180 mg/m2; leucovorin, 400 mg/m2; fluorouracil, 400 mg/m2 (intravenous push);
fluorouracil, 2400 mg/m2 (infused); and
bevacizumab, 5 mg/kg. On day 11 after the
FOLFIRI/bevacizumab infusion, the patient was hospitalized for neutropenic fever, thrombocytopenia, anemia, and diarrhea. On day 15, the patient awoke with
a headache and bilateral cortical blindness. Magnetic resonance imaging revealed patchy areas of increased fluidattenuated inversion recovery signal
intensity in the occipital and posterior
parietal lobes, consistent with RPLS
(Figure 1). The patient’s blood pressure
during hospitalization was mildly elevated (systolic blood pressure range, 140150 mm Hg), which was aggressively
treated subsequent to the vision loss. A
qualitative urine assessment revealed proteinuria, which was not present before the
initiation of FOLFIRI/bevacizumab chemotherapy. Other laboratory values included hematocrit, 28.3% (pre-FOLFIRI/
bevacizumab therapy level, 28.6%), which

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Figure 1. Fluid-attenuated inversion recovery magnetic resonance image
taken the day of neurologic symptom development shows a bilateral occipital
and posterior parietal abnormality.

Figure 2. Fluid-attenuated inversion recovery magnetic resonance image
taken 1 week after neurologic symptom development. There was interval
improvement of occipital and parietal hyperintensities.

was normal; serum urea nitrogen and creatinine levels
were also measured, liver function testing was performed, and a peripheral blood smear was obtained. On
day 17, the patient developed transcortical global aphasia with intermittent spells of confusion and agitation.
By day 18, his speech and visual disturbance began to
improve. On day 19, he experienced a generalized tonicclonic seizure. A diagnostic lumbar puncture showed a
normal opening pressure and normal cerebrospinal microscopic and biochemistry results. Subsequent magnetic resonance imaging on day 19 showed interval improvement in fluid-attenuated inversion recovery
hyperintensities (Figure 2). By day 25, the patient’s neurologic deficits had completely resolved.
Over the next 6 weeks, the patient developed new bony
lesions involving the thoracic and lumbar vertebrae, with
cord compression. Treatment was initiated with corticosteroids and palliative radiation. No further chemotherapy cycles were given, and no further neurologic spells
occurred.

clinical improvement correlated with radiographic occipital lobe edema resolution. Although not entirely understood, the mechanism of RPLS is considered to be
secondary to failed autoregulation of cerebral blood
flow leading to cerebral vasogenic edema.1-4 Failed cerebral vascular autoregulation results in hyperperfusion
and dilation of cerebral arterioles, disruption of the endothelium, immediate breakdown of the blood-brain
barrier, and, finally, transudation of plasma and red
blood cells into the interstitium. A relative paucity of
sympathetic adrenergic innervation to the vertebralbasilar system is suggested to account for the tendency
for this syndrome to involve structures supplied by the
posterior circulation.5,6 Hypointense T1 lesions and hyperintense T2 lesions are often seen bilaterally in occipital and parietal lobe white matter. Predisposing factors consistent with this proposed mechanism of
vascular dysregulation have been described by Tam and
colleagues,2 who regard patients with significant fluid
overload (⬎10% of the baseline weight), a mean blood
pressure higher than 25% of baseline, and a creatinine
level greater than 1.8 mg/dL (⬎160 µmol/L) to be high
risk for RPLS.
Toxic damage to the vascular endothelium or bloodbrain barrier caused by immunosuppressant and cytotoxic medications is further postulated to contribute to
the pathophysiological features of RPLS. 1,2,7 Direct
causal relationships between chemotherapy agents and
RPLS have been difficult to establish, and the correlation is more common with cyclosporine and tacrolimus.
Other associated agents include methotrexate; the alpha

COMMENT

The onset and resolution of cortical blindness and seizure activity observed in our patient correlated with the
radiographic abnormalities and were consistent with
the natural history of RPLS. The focal nature and immediate onset of our patient’s visual disturbance might
suggest that an ischemic event had occurred. However,
imaging studies pointed to vasogenic edema as the chief
cause, rather than infarction. Furthermore, the patient’s
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interferons; cisplatin; cytarabine; cyclophosphamide,
doxorubicin hydrochloride (Adriamycin), vincristine
sulfate (Oncovin), and prednisone; or combinations
involving doxorubicin, ifosfamide, and etoposide.
While we cannot be certain of the causal relationship
between bevacizumab and the RPLS in our patient, it
seems most likely by the following process of elimination: the chemotherapeutic regimen in our patient also
consisted of FOLFIRI. The cerebral toxicity of fluorouracil, although rare, is well described as a multifocal
inflammatory leukoencephalopathy. 8,9 Multifocal
inflammatory leukoencephalopathy typically develops 6
weeks to 5 months after the initiation of combination
chemotherapy with levamisole hydrochloride and fluorouracil. Multifocal inflammatory leukoencephalopathy
is a clinically and radiographically distinct syndrome
from RPLS, making it unlikely that fluorouracil caused
our patient’s syndrome. To our knowledge, no reports
in the literature associate irinotecan, a type I topoisomerase inhibitor, with the development of RPLS or other
encephalopathy syndromes. Leucovorin, a derivative of
folic acid, would not be expected to contribute to the
development of RPLS. During the review of this report,
several other investigators10 observed an association
between RPLS and bevacizumab administration.
Bevacizumab, a monoclonal antibody against VEGF,
has recently been approved as a first-line treatment for
patients with metastatic colorectal cancer when administered in combination with FOLFIRI.11 Vascular endothelial growth factor is a naturally occurring, endothelial, cell-specific glycoprotein that stimulates blood
vessel formation and has been implicated in tumor
growth and spread. Nitric oxide and prostacyclin production are enhanced by VEGF, thus promoting vasodilation.12 The effects of VEGF inhibition on the systemic endothelium have been described.13 Soluble fms-like
tyrosine kinase 1 is a naturally occurring VEGF antagonist expressed by the placenta and is thought to produce an antiangiogenic state by binding VEGF and placental growth factor. Vascular endothelial growth factor
and placental growth factor bound to soluble fms-like tyrosine kinase 1 render them biologically inactive, thus
inducing endothelial cell dysfunction.13,14 Animal studies by Sugimoto and colleagues15 demonstrated that administration of anti-VEGF antibodies and soluble fmslike tyrosine kinase 1 resulted in glomerular endothelial
cell detachment and hypertrophy. The resulting glomerular endotheliosis has been suggested to be responsible
for the hypertension and proteinuria commonly seen in
preeclamptic patients.13,15 Furthermore, alterations in angiogenic factors have been postulated to disrupt normal
systemic endothelial cell function and increase the cerebral vascular permeability of the blood-brain barrier,
thus contributing to RPLS in preeclamptic patients.16 The
precise role of the antiangiogenic and angiogenic factors, soluble fms-like tyrosine kinase 1, VEGF, and placental growth factor, remains under investigation.
Bevacizumab is a potent inhibitor of VEGF function,
disrupting angiogenesis and depriving tumors of their
blood supply.17,18 Angiogenesis inhibitors are thought to
be beneficial in cancer treatment by normalizing patho(REPRINTED) ARCH NEUROL / VOL 63, OCT 2006
1477

logic tumor vasculature and restoring proangiogenic and
antiangiogenic factors and, thereby, allowing for more
efficient delivery of chemotherapeutic agents to tumors.19,20 Hypertension and proteinuria are commonly
reported adverse effects of bevacizumab.21 We suggest that
the development of RPLS in our patient may have been
secondary to bevacizumab. Several mechanisms may be
contributory. First, bevacizumab may have contributed
to the patient’s hypertensive state in an otherwise nonhypertensive patient, because hypertensive crises are
known adverse effects of this medication. Although our
patient had a mean blood pressure higher than 25% of
baseline, he was not otherwise at high risk for the development of RPLS. He was not hypervolemic, and his
serum creatinine level was normal. Second, a global endothelial cell dysfunction induced by bevacizumab may
have led to RPLS. Although microangiopathic hemolytic anemia was not suggested by our patient’s blood
smear result, hypertension and proteinuria were present. We speculate that inhibition of VEGF induced systemic endothelial cell dysfunction and, in particular, that
of the cerebral vasculature, which, when exposed to moderately elevated perfusion, was unable to appropriately
accommodate. The induction of RPLS in our patient and
possibly in preeclamptic patients may be secondary to
this mechanism.
We postulate that the RPLS in our patient resulted from
systemic endothelial cell dysfunction induced by bevacizumab. A more detailed understanding of the mechanism of VEGF modulators on the cerebral vasculature is
needed. Regardless, high clinical suspicion is encouraged toward patients presenting with symptoms characteristic of RPLS while receiving bevacizumab, particularly when in combination with FOLFIRI therapy. Prompt
recognition of this syndrome will allow initiation of immediate treatment and appropriate alterations in chemotherapy regimens.
Accepted for Publication: May 15, 2006.
Correspondence: Peter R. Bergethon, MD, Department
of Anatomy and Neurobiology, Boston University School
of Medicine, 715 Albany St, Boston, MA 02118 (prberget
@bu.edu).
Author Contributions: Study concept and design: Allen
and Bergethon. Acquisition of data: Allen. Analysis and interpretation of data: Allen, Adlakha, and Bergethon. Drafting of the manuscript: Allen, Adlakha, and Bergethon. Critical revision of the manuscript for important intellectual
content: Allen, Adlakha, and Bergethon. Administrative,
technical, and material support: Allen and Bergethon. Study
supervision: Bergethon.
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3. Garg RK. Posterior leukoencephalopathy syndrome. Postgrad Med J. 2001;77:
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