J Neurosurg 116:972–977, 2012

Bevacizumab used for the treatment of severe, refractory
perilesional edema due to an arteriovenous malformation
treated with stereotactic radiosurgery
Case report
Brian J. Williams, M.D., Deric M. Park, M.D., and Jason P. Sheehan, M.D., Ph.D.
Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
The authors present a case of an arteriovenous malformation of the central sulcus treated with Gamma Knife
surgery. The patient developed perilesional edema 9 months after treatment and experienced severe headache and
hemiparesis. Her symptoms were refractory to corticosteroid therapy and pain management. She was subsequently
treated with bevacizumab with striking improvement in her symptoms and results of neuroimaging studies. This is
the first time that bevacizumab has been used to control severe refractory perilesional edema related to an intracranial
arteriovenous malformation.
(http://thejns.org/doi/abs/10.3171/2012.1.JNS111627)

Key Words • bevacizumab
stereotactic radiosurgery

P

•

arteriovenous malformation •

erilesional edema is a significant clinical prob-

lem. An agent that reliably abrogates this edema is
dexamethasone, a potent glucocorticoid receptor
agonist.14 Animal and in vitro data indicate that VEGF is
the primary mediator of peritumoral edema.2,19,20 Dexamethasone is believed to act primarily through the glucocorticoid receptor to decrease the expression of VEGF
and thereby edema.12 Bevacizumab, a monoclonal antibody against VEGF, has been used in the treatment of
recurrent glioblastoma.8,15,21,24 Recently, bevacizumab has
been successfully used to control perilesional edema related to radiation necrosis, in a double-blind randomized,
controlled trial.9,10,16,17,23 All patients included in this trial
had neoplastic lesions.
The use of bevacizumab for vascular pathology has
been reported in Osler Weber Rendu Syndrome (Hereditary Hemorrhagic Telangectasia) to decrease the incidence of epistaxis in these patients.1,3,7,13,22 However, bevacizumab has not been used to treat AVMs of the central
nervous system or related perilesional edema after treatment with SRS.
Abbreviations used in this paper: AVM = arteriovenous malformation; GKS = Gamma Knife surgery; SRS = stereotactic radiosurgery; VEGF = vascular endothelial growth factor.

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edema

•

We report the first case of the use of bevacizumab
to control symptomatic perilesional edema refractory
to corticosteroid therapy after GKS for an intracranial
AVM.

Case Report

This 20-year-old right-handed woman had an AVM
centered on the right central sulcus, which was found during an evaluation for persistent headaches. The malformation measured 1.4 cm in maximum dimension and was
located on the motor strip (Fig. 1). After discussion of the
risks and benefits of the treatment options, she elected to
proceed with GKS. She was treated with a prescription
dose of 22.0 Gy to the 50% isodose line with a maximum dose of 44.0 Gy. The planned treatment volume was
2.53 ml (Fig. 2). She initially did well and was discharged
home the day after her procedure in good condition. She
presented to the emergency department 9 months after GKS complaining of 2–3 weeks of severe persistent
right-side headache and difficulty walking in high heels.
This article contains some figures that are displayed in color
on­line but in black-and-white in the print edition.

J Neurosurg / Volume 116 / May 2012

Bevacizumab treatment of edema from an AVM treated with SRS

Fig. 1. Digital subtraction angiography and MRI of the AVM of the right central sulcus prior to GKS. Digital subtraction angiography is shown with right internal carotid artery injection in anteroposterior (B and D) and lateral projections (A and C) in
the arterial phase (A and B) and capillary phase (C and D), demonstrating shunting in the middle cerebral artery territory and
an early draining vein into the superior sagittal sinus. In addition, a stereotactic, axial T1-weighted MR image obtained after Gd
administration (E) demonstrated a contrast-enhancing vascular lesion consistent with an AVM in the region of the central sulcus.

Fig. 2. Dose treatment plan from GKS treatment session using the GammaPlan software, including both the stereotactic MR
and digital subtraction angiograms. The 50% isodose line is shown in yellow.

J Neurosurg / Volume 116 / May 2012

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B. J. Williams, D. M. Park, and J. P. Sheehan
Her neurological examination was remarkable for weakness 4/5 in the left arm and 4+/5 in the left leg. An MRI
demonstrated increased T2 signal intensity surrounding
the AVM (Fig. 3). Corticosteroid therapy was initiated at
that time, with a prescription for slow tapering off of the
dosage over a month. The patient experienced a partial
clinical response to the steroids with slight improvement
in her headache but minimal change in her weakness.
After 3 weeks, while on a lower dose of steroid medication, she returned to the emergency department with
severe headache, nausea, vomiting, and unchanged weakness. She subsequently developed a left-sided pronator
drift. An MRI study demonstrated persistent perilesional
edema (Fig. 4). She was restarted on a high-dose steroid
taper, and vitamin E and pentoxifylline were added. She
continued to experience severe headaches intermittently;
her hemiparesis remained stable. Approximately 1 month
later (2 months after the onset of her symptoms) her
headaches became severe enough to restrict her activity
to bed rest only, causing her to present to the emergency
department again. Her neurological examination findings
were stable. Both MRI and CT demonstrated persistent
perilesional edema (Fig. 5). She was admitted to the hospital and treated with an increased dose of corticosteroids
without significant improvement in her symptoms. Her
severe headache, which was refractory to pain management with intravenous narcotics and steroids, kept her incapacitated and essentially bed bound.
Considering the inadequate response to corticosteroids and her severe refractory symptoms, we discussed
the option of treating the perilesional edema with bevacizumab. After informed consent was obtained, the patient was initially treated with a dose of 2.5 mg/kg, which
she tolerated without incident. She experienced dramatic
improvement in her headache the day after her infusion.
She was able to ambulate without assistance and did not
require further intravenous narcotic therapy. One week
later she returned for evaluation and additional treatment.
A CT study demonstrated no complications from treatment with her initial dose, and therefore, a dose of 7.5 mg/
kg was administered (Fig. 6). On follow-up at 2 weeks
(Fig. 7) and 6 weeks (Fig. 8) after the initial infusion of
bevacizumab, her symptoms continued to improve. Her
headache was intermittent and tolerable, managed with
tramadol, and her steroid had been tapered off. Her weakness had improved to 4+/5 in her left lower extremity. She
continued to have a pronator drift and slight hyperreflexia
on the left. At 2 weeks’ follow-up, MRI demonstrated
stable perilesional edema on T2-weighted images, and
MR angiography demonstrated no abnormal shunting in
the region of the AVM (Fig. 7). A CT study and MRI
performed at 6 weeks after the initial administration of
bevacizumab demonstrated a dramatic decrease in contrast enhancement in the area of the AVM and a decrease
in T2 signal around the AVM (Fig. 8). Follow-up at 1 year
after GKS treatment and 10 weeks after the administration of bevacizumab demonstrated clinical improvement
with infrequent use of tramadol for headache and no use
of steroid agents. Neurological examination showed 4+/5
strength in the left arm and leg and a slight left pronater
drift. She was able to return to school and activities of
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Fig. 3. Axial MR images obtained 9 months after GKS at the time
of the patient’s initial presentation to the emergency department. A T1weighted postcontrast image (left) demonstrating enhancement in the
area of the AVM with surrounding hypointensity and a T2-weighted image (right) demonstrating T2 hyperintensity correlating with T1 hypointensity consistent with edema.

daily living without difficulty. Digital subtraction angiography performed at this time demonstrated obliteration
of the AVM nidus with no evidence of abnormal shunting
(Fig. 9).

Discussion

Radiation-induced MRI changes occur in 36% of
AVM cases treated with SRS at our institution.25 These
changes typically occur between 6 and 25 months after
treatment and last for 2 to 79 months. The MRI findings
were not associated with symptoms in 17% of cases, and
these cases were managed expectantly. Symptomatic patients presented with headaches and new neurological
deficits, as in our report, and were generally treated only
with corticosteroid therapy.25,26 In these cases perilesional
edema typically heralded obliteration of the malformation. In the case presented in this report, the AVM was in
an eloquent area, thus the patient developed a focal neurological deficit. Her severe headache, which was the most
functionally limiting symptom, was a significant clinical
feature as well.

Fig. 4. Images obtained 1 month after the patient’s initial presentation to the emergency department and 10 months after GKS. Axial
T1-weighted post-contrast (left) and T2-weighted (right) MR images
demonstrating persistent perilesional edema of the pre- and postcentral
gyri as well as the centrum semiovale.

J Neurosurg / Volume 116 / May 2012

Bevacizumab treatment of edema from an AVM treated with SRS

Fig. 5. Images obtained 1 day prior to administration of bevacizumab, which was 2 months after the patient’s initial presentation to the emergency department. Axial CT image (A), T1-weighted post-contrast MR image (B), and T2-weighted MR image (C)
demonstrating unchanged perilesional edema.

Bevacizumab has been used successfully for severe,
symptomatic perilesional edema related to radiation necrosis from fractionated external beam treatments.9,10,17,23
If VEGF is a final common mediator of perilesional edema due to tumors, necrosis, or AVMs treated with radiosurgery, then there may be a rational basis for using bevacizumab in these cases.18 The side effect profile and cost
of bevacizumab limit its potential use for this indication
given that corticosteroids are inexpensive and typically
control perilesional edema safely and effectively.6,8,11,15
Nevertheless, in cases in which edema is refractory to
corticosteroids and the patient is symptomatic, it may be

reasonable to consider the use of bevacizumab, especially
when symptoms are severe and operative intervention
would have significant morbidity, as in our case.
The administration of this medication should be supervised by clinicians familiar with prescribing this medication and with the pertinent side effects. In particular,
the risk of bevacizumab in patients with vascular malformations known to have a tendency to hemorrhage must be
weighed against the benefits and alternative therapeutic
options (for example, open resection or continued management with narcotic and corticosteroid agents). When
bevacizumab is used in GKS patients with posttreatment edema and necrosis, the patients must be monitored
closely with clinical examination and serial imaging for
improvement in the edema and potential development of
bevacizumab-associated toxicity. Common severe adverse
events associated with the use of bevacizumab are seizure
(6%), fatigue (3.6%), hypertension (8.3%), and neutropenia, diarrhea, and pneumonia (1.2% each).5 Specifically
related to neurosurgical complications, bevacizumab has
been associated with worse wound healing if given before
a procedure compared with healing in groups not treated
with bevacizumab or treated postoperatively.4

Conclusions

We report the first case of bevacizumab used for

Fig. 6. A CT image obtained 1 week after administration of the first
dose of bevacizumab (2.5 mg/kg) demonstrating mildly improved perilesional edema and no evidence of hemorrhage in or around the lesion.

J Neurosurg / Volume 116 / May 2012

Fig. 7. Imaging obtained 2 weeks after administration of the first
dose of bevacizumab. Axial T2-weighted MR image (left) and reconstructed MR angiographic (right) image demonstrating stable perilesional edema compared with the previous CT scan and no evidence of
shunting in the region of the AVM.

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B. J. Williams, D. M. Park, and J. P. Sheehan

Fig. 8. Computed tomography and MR images obtained 6 weeks after administration of the first dose of bevacizumab demonstrating resolution of perilesional edema. Axial CT image (A), T1-weighted post-contrast MR image (B), and T2-weighted MR
image (C) demonstrating dramatic improvement in the perilesional edema and decreased enhancement in the region of the AVM.

treatment of corticosteroid-refractory, symptomatic, and
progressive edema due to an AVM after GKS. Given that
this is a single case report, we cannot presume to provide proof of a causal relationship between bevacizumab
and the resolution of perilesional edema. However, when
evaluated in the context of the recent trial of bevacizumab
for perilesional edema related to radiation necrosis, this
case provides further evidence that bevacizumab may be
a useful tool in the armamentarium of clinicians treating
these difficult cases. Based on this evidence, we believe
that the efficacy and safety of bevacizumab should be rigorously evaluated for severe, refractory cases of perilesional edema.
Disclosure
Dr. Park is a consultant for Elekta.
Author contributions to the study and manuscript preparation
include the following. Conception and design: all authors. Ac­qui­
sition of data: Williams. Drafting the article: all authors. Critically
re­vising the article: all authors. Reviewed submitted version of man­
uscript: all authors. Approved the final version of the manuscript on
behalf of all authors: Sheehan.

Fig. 9. Anterior-posterior (left) and lateral (right) projection digital
subtraction angiograms obtained 1 year after GKS of the AVM near the
right central sulcus demonstrating obliteration of the AVM nidus and no
evidence of shunting in the region of the malformation.

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Manuscript submitted September 15, 2011.
Accepted January 9, 2012.
Please include this information when citing this paper: published
online February 10, 2012; DOI: 10.3171/2012.1.JNS111627.
Address correspondence to: Jason P. Sheehan, M.D., Ph.D.,
Uni­versity of Virginia Health System, Department of Neurological
Surgery, Charlottesville, Vir­ginia 22908. email: jps2f@virginia.edu.

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