Time-Staged Gamma Knife Stereotactic Radiosurgery for Large Cerebral Arteriovenous Malformations: A Preliminary Report
Time-Staged Gamma Knife Stereotactic Radiosurgery for Large Cerebral Arteriovenous Malformations: A Preliminary Report
Hye Ran Park 1 2
Jae Meen Lee 0 1
Jin Wook Kim 0 1
Jung-Ho Han 1
Hyun-Tai Chung 0 1
Moon Hee Han 1
Dong Gyu Kim 0 1
Sun Ha Paek 0 1
Nader Pouratian, University of California
Los Angeles, UNITED STATES
0 Department of Neurosurgery, Seoul National University Hospital , Seoul , Republic of Korea, 3 Department of Neurosurgery, Seoul National University Bundang Hospital , Seoul , Republic of Korea, 4 Department of Radiology, Seoul National University Hospital , Seoul , Republic of Korea
1 was supported by the Korea Institute of Planning & Evaluation for Technology in Food , Agriculture, Forestry, and Fisheries , Republic of Korea (311011-05-3-SB020) , by the Korea Healthcare Technology R&D Project (HI11C21100200) funded by Ministry of Health & Welfare, Republic of Korea, by the Technology Innovation Program (10050154, Business Model Development for Personalized
2 Department of Neurosurgery, Soonchunhyang University Hospital , Seoul , Republic of Korea
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Medicine Based on Integrated Genome and Clinical
Information) funded by the Ministry of Trade,
Industry & Energy (MI, Korea), and by the Bio &
Medical Technology Development Program of the
NRF funded by the Korean government, MSIP
(2015M3C7A1028926). The funders had no role in
study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
Time-staged GKS could be an effective and safe treatment option in the management of
Arteriovenous malformation (AVM) is the second most common cause of intracerebral
hemorrhage in people <35 years of age, following trauma [
]. Treatment options for cerebral AVM
include surgery, endovascular treatments, and radiosurgery. Among these, stereotactic
radiosurgery (SRS) has proven beneficial in the treatment of small- to medium-sized AVMs,
reducing the risk of future intracranial bleeding with minimal treatment-related morbidity [
cure rate in properly selected patients who undergo SRS reaches approximately 80–85%.
However, radiosurgery is generally recommended only for AVMs with an average
maximum diameter 3 cm. The management of large AVMs remains challenging, and patients
with large and, asymptomatic AVMs are usually managed conservatively because the risk
associated any intervention including embolization, surgical resection, and/or radiosurgery may be
equal to or greater than that arising from the natural history of the AVM if left untreated.
Although SRS has been used as the alternative option, its use is limited; single-stage SRS for
large volume AVMs is associated with a low rate of obliteration or unacceptable adverse
radiation effects (AREs). Optimal radiation doses, considered necessary to completely obliterate the
nidus with a single gamma knife stereotactic radiosurgery (GKS) session, cannot be delivered
in some cases in which there is a relatively large nidus. AVMs exceeding 3 cm or 10 cm3 in
diameter and volume, respectively are traditionally not considered appropriate candidates for
radiosurgical treatment, due to their lower obliteration rates [
In this retrospective study, we describe the outcomes of patients with large AVMs who
underwent time-staged GKS at a single institution. Time-staged GKS was defined as repeated
treatment of the entire nidus using low doses for each stage over an interval period of 3 to 4
years. We evaluated the obliteration rates, risk of post-GKS hemorrhage and complications.
Patients and Methods
This retrospective study was approved by the institutional review board of our institution (IRB
No. 1508-109-696). The requirement for obtaining informed consent from the patients was
waived because the study was based on the information obtained as a part of routine clinical
care and medical records. We retrospectively reviewed the data of 48 patients who underwent
time-staged GKS for cerebral AVMs 10 cm3 between March 1998 and December 2011. Three
patients who did not undergo at least 6 months of clinical follow-up or one session of magnetic
resonance imaging (MRI) were excluded. The remaining 45 patients were enrolled; their
baseline characteristics at the time of initial radiosurgery are summarized in Table 1.
The patients were carefully selected for radiosurgery by experts in neurosurgery and
radiosurgery. Radiosurgery was recommended for those considered to have high rates of morbidity
or mortality associated with surgical resection under general anesthesia.
Radiosurgery was performed in patients under local anesthesia, supplemented with
intravenous sedation. Patients were treated using the Leksell Gamma Knife (model B or C, Elekta
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*Radiorusrgery-based AVM scale = (0.1)(volume,mL) + (0.02)(age,yr)+(0.3)(location, hemispheric/corpus callosum/cerebellar = 0; basal ganglia/thalamus/
brainstem = 1)
3 / 13
Instrument AB) with Leksell Gamma Plan (Elekta, Stockholm, Sweden). Treatment planning
was based on the combination of stereotactic biplanar angiography and thin-slice MRI.
Imageintegrated treatment planning was performed by neurosurgeons and interventional
The GKS isodose, maximum dose, and marginal dose were initially decided based on AVM
volume and were calculated during dose planning with the best-fit isodose method. When
selecting a radiation dose, we referred to the guideline of the Kjellberg 1% isoeffective line for
cerebral necrosis after proton-beam radiosurgery [
], and optimized the dose by reducing it
based on the location of the AVM. The prescribed dose was decreased preferably to nearly 10
Gy for large (volumes 10 cm3) and extra-large (volumes 14 cm3) AVMs, which was used as
the lowest dose to obtain any obliteration response using GKS [
]. The treatments were
designed to deliver 50% of the maximum dose to the margins of the lesion.
Patients were clinically evaluated at 6 months, 1, 2, and 3 years after GKS. MRI was
recommended every 6 months. Angiography was recommended at 3 years after radiosurgery, but it
was performed earlier in patients whose AVM nidus had disappeared on MRI. Complete AVM
obliteration was defined as an absence of abnormal vessels in the former nidus of the AVM, the
disappearance or normalization of draining veins, and normal circulation time based on the
result of angiography. In patients who did not undergo angiography, AVM obliteration was
defined as a disappearance of the nidus in enhanced T1- and T2-weighted images and an
absence of flow-void signal abnormalities in T2-weighted images on MRI. We determined
AVM nidus obliteration based on both MRI and angiography. If the neuroimaging study
performed 3 years after GKS revealed a residual nidus, repeated radiosurgical treatment was
simultaneously recommended with consideration for the size and location of the residual
AVM. The follow-up protocol and definition of outcome used for repeated treatments were the
same as those for primary AVM radiosurgery. The final follow-up imaging modality since the
last GKS session was MRI in 22 patients (48.9%) and angiographyin 23 patients (51.1%).
Post-GKS hemorrhage was defined as a clinically symptomatic event such as headache,
seizure, or loss of consciousness, or focal deficits along with signs of acute hemorrhage detected
by means of computed tomography (CT) or MRI. PRI changes included postradiosurgical
edema, radiation necrosis, and delayed cyst formation on T2-weighted and/or FLAIR MRI.
Information about all patients was recorded in a radiosurgical database at the time of their
treatment and at each clinical follow-up visit.
Statistical analyses were performed using SPSS version 18.0 (SPSS, Inc., Chicago, IL, USA). A
two-sided P value of < 0.05 was considered to indicate statistical significance.
2-stage GKS (n = 37)
6.97 ± 6.92(range,
17.0 (range, 7±21)
23.90 ± 6.50 (range,
12.25 (range, 10±15)
3-stage GKS (n = 8)
19.43 ± 7.46 (range,
13.5 (range, 12±15)
50 (range, 50)
50 (range, 49±50)
50 (range, 49±50)
7.48 ± 6.86 (range,
15.5 (range, 12.5±
50 (range, 50)
18.5 (range, 7±23)
96.5 (range, 95.0±
remnant AVM was 6.97 ± 6.92 cm3 (range, 0.37–25.1 cm3). The mean remnant nidus volume
percent compared to the initial volume was 43.63 ± 37.28%. The patients underwent the 2nd
GKS session with the following median parameters: marginal dose 17 Gy (range, 7–21), isodose
line 50%, shot 12 (range, 3–31), and covered ratio 97% (range, 93–99). The median interval
between the 2nd GKS session and the final imaging follow-up was 44 months (range, 6–136).
Among these 37 patients, 24 patients (64.9%) obtained complete obliteration. The remnant
nidus volume percent compared to the initial volume in the remaining 13 patients was
10.9 ± 6.5%. These 13 patients who failed to achieve complete obliteration obtained
considerable volume reduction. Fig 1 presents the volume percent at each GKS session for individual
Five patients underwent 3-stage GKS for AVM with a volume 10 cm3. The mean AVM
volume at the time of each GKS session was as follows: 1st GKS session, 23.90 ± 6.50 cm3 (range,
10.50–7.46 cm3); 2nd GKS session, 19.43 ± 7.46 cm3 (range, 10.50–28.20 cm3), 3rd GKS session,
7.48 ± 6.86 cm3 (range, 0.54–17.41 cm3). The median interval durations between the 1st and
2nd GKS sessions, and the 2nd and 3rd GKS sessions were 37.5 (range, 32–46) and 38 (range,
35–68) months, respectively. The marginal dose in each GKS sessions gradually increased; 1st
GKS session, 12.25 Gy (range, 10–15); 2nd GKS session, 13.5 Gy (range, 12–15); 3rd GKS
session, 15.5 Gy (range 12.5–18). Finally, after a median follow-up duration of 47.5 months
(range, 15–70) following the 3rd GKS session, 5 patients achieved complete obliteration
(complete obliteration rate, 62.5%). The remaining 3 patients also experienced substantial volume
reduction; the remnant nidus volume percent compared to the initial volume was 39.8%,
21.5%, and 2.98%, respectively. Fig 2 presents the volume percent at each GKS session for these
five patients. One patient experienced transient volume increase after the 1st GKS session
without any relevant symptom. This transient volume increase was thought to be caused by the
change of flow dynamics within AVM, and the following imaging study revealed decrease of
Overall treatment response and clinical outcome
The overall obliteration rate of AVM nidus was 64.4%, and the remnant nidus volume percent
compared to the initial volume was 12.9 ± 9.9% (range, 2.8–39.8) in the non-obliteration
group. The median period between the 1st GKS session and AVM obliteration was 76.50 ±
28.03 months (range, 39–173) in the 2-stage GKS group and 115.0 ± 13.8 months (range, 90–
5 / 13
Fig 1. The volume percent at each gamma knife radiosurgery (GKS) session of the 37 patients who
underwent 2-stage GKS
128) in the 3-stage GKS group. Coexisting aneurysm was the only significant factor correlated
with AVM obliteration (P = 0.013, Exp(B) = 0.038, multivariate analysis) in both univariate
and multivariate analysis (Table A in S1 Table).
Fig 2. The volume percent at each gamma knife radiosurgery (GKS) session of the 8 patients who
underwent 3-stage GKS
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The seizure-free and seizure medication-free rate was 84.4% and 68.9%, respectively. Table B
in S1 Table summarizes the prognostic factors associated with seizure-free and seizure-free
outcome. There was no factor that significantly correlated with seizure freedom. However, AVM
nidus obliteration was significantly associated with being seizure medication-free (P = 0.023, Exp
(B) = 0.023, multivariate analysis) in both univariate and multivariate analysis. Of the 9 patients
who presented with seizure as the initial presentation, 6 (66.7%) obtained seizure-free status of
Engel classification I. The remaining 3 patients are taking anti-epilepsy drugs.
The mean final KPS score was 95.33 ± 15.46 points, and 40 patients (88.9%) returned to
their work at the final clinical follow-up points. Table 3 represents pre- and post-treatment
mRS (modified Rankin Scale) scores. Twenty-nine patients (64.4%) showed no change on
mRS. Eleven patients (24.4%) had higher mRS scores, and 5 patients (11.1%) had improvement
We referred Pollock and Flickinger’s outcome criteria and stratified the outcomes. [
Patients’ outcome was stratified as excellent, good, fair, unchanged, poor, or death, based on
the last follow-up review. Twenty-one patients (47%) had an excellent outcome which defined
as complete nidus obliteration and no new development of neurological deficit. Six patients
(13%) and 2 patients (4%) with complete nidus obliteration were classified as a good outcome
with minor deficit that did not interfere with normal daily life and a fair outcome with major
deficit causing a decline in the patient’s level of functioning, respectively. Fifteen patients
(33%) had an unchanged outcome which was defined as persistent arteriovenous shunting
without new neurological deficit. No patient was classified as poor outcome with a new
neurological deficit and incomplete nidus obliteration. One patient (2%) died.
The median modified radiosurgery-based AVM score (RBAS) was 2.60 (range, 1.37–4.77).
4, 8, 9
] Univariate linear regression showed a statistically significant correlation between
RBAS and excellent outcome (1.01–2.00, 85.7%; 2.01–3.00, 48.0%; 3.01–4.00, 25.0%; >4.00,
0%; F = 11.200, R2 = 0.160, P = 0.006; Fig 3).
Post-GKS complications and additional treatment after GKS
Complications included post-GKS hemorrhage (5 patients, 11.1%) and post-radiosurgical
imaging change (19 patients, 42.2%). The median interval period between the 1st GKS session
and the occurrence of hemorrhage was 54 ± 43 months (range, 32–140). Except for one patient
who died of intracerebral hemorrhage, the other four patients experienced minor bleeding and
recovered after management. One patient harbored intraventricular and intracerebral
hemorrhage 27 months after the 2nd GKS session, and emergent extraventricular drainage (EVD) was
performed. However, angiography performed 17 days after hemorrhage occurrence revealed
no remnant AVM nidus. Another patient received ventriculo-peritoneal shunt due to
Fig 3. Graph showing relationship between modified radiosurgery-based AVM score (RBAS) and the percentage of
patients who obtained an excellent outcome at the last follow-up. R2 = 0.160, p = 0.006.
combined hydrocephalus lead performed normal daily life. Stereotactic hematoma removal
was required in one patient, and he achieved full recovery. Post-radiosurgical imaging changes
included postradiosurgical edema, radiation necrosis, and delayed cyst formation on
T2-weighted and/or FLAIR MR Images. Any clinically meaningful event associated with
postradiosurgical imaging change was not noted.
Management of large AVM
A Randomized Trial of Unruptured Brain AVMs (ARUBA) was a prospective, multicenter
trial that randomized 223 patients with unruptured AVMs to medical or interventional
therapy. ARUBA was terminated early because interventional therapy showed an inferior outcome
compared with medical treatment [
]. However, considering the higher risk of future
hemorrhage and associated morbidity of a large AVM, if an alternative optimal treatment option can
be developed, the benefit of treating large AVMs might outweigh the risk of treatment.
Surgical resection is the widely used treatment option for AVMs. It provides a distinct
advantage of complete removal in a single or staged operation. However, surgery is far less
attractive for large AVMs due to higher rates of morbidity and mortality. Additionally, there is
an inherent risk of normal perfusion pressure breakthrough with larger lesions, and the risk of
future hemorrhage is increased in partially treated lesions [
]. For this reason, surgery is not
solely performed for treating large AVMs without other supportive managements.
The reported rates of complete radiological obliteration of AVMs in patients treated with
SRS ranges from 50% to 80% [
]. However, the outcomes of SRS for large AVMs have been
disappointing. The patients with a larger AVM tended to show lower obliteration rates than
those with a smaller AVM . Single-session radiosurgery often does not yield a complete
8 / 13
cure, and so is not recommended for lesions 3 cm in diameter or 10 cm3 in volume by most
]. Higher complication rates for large AVMs after GKS, such as post-radiosurgical
MRI abnormalities and radiation necrosis have been reported, because of the higher dose
needed to cover the lesion [
Previous authors have reported postradiosurgical complications including symptomatic
sequelae (9%-11%), postirradiation imaging change up to 30% such as white matter disease,
edema, or necrosis, and post-radiosurgical hemorrhage [
]. The risk of radiation injury
resulting in a permanent neurologic deficit is reportedly 2% to 3% for single-session SRS for AVMs
]. Han et al. demonstrated an annual risk of 10.4% for patients who received incomplete
]. One of the major drawbacks of SRS for AVMs is the presence of a latency
period (mean, 2–3 years) before full biologic effects occur. During this latency period, partial
treatment results in compartmental cytoarchitectural changes, and the risk of hemorrhage still
persists. The risk of secondary malignancy after SRS is less than 1/1000 with a follow-up
duration of more than 5 years .
To overcome the forementioned limitations of single-session SRS for AVM, a new approach
including staged GKS has been attempted. Volume-staged radiosurgery has been regarded as
an alternative option for single modality treatment [
]. Pollock et al. targeted different volume
compartments, and performed staged radiosurgery for small, medium, and large AVMs. They
compared volume-staged SRS to hypothetical single-session procedures and found that volume
staging resulted in less radiation exposure to the adjacent brain [
The disadvantage of volume-staged GKS is a longer latency period between treatments [
Volume-staged GKS is considered to be associated with greater risk of hemorrhage due to the
latency period of 3–6 months. An increased risk of hemorrhage resulting from redistribution
of blood flow to non-irradiated regions has been described [
Time-staged GKS for treating a large AVM
The dilemma in radiosurgical treatment of large AVM is the inverse proportion relationship
between the obliteration and the complication according to the prescribed dose. Time-staged GKS
was introduced to achieve dose reduction in order to reduce the adverse radiation effects. After
the 1st GKS session with a low dose of 12–13 Gy covering the whole lesion, there is a waiting
period of about 3–4 years. The occurrence of radiobiological repair is expected during this waiting
period. Theoretically, post-irradiation radiobiological repair may occur quite quickly; hence,
radiosurgical treatment can be repeated within only 3–6 months [
]. The nidus is expected to
become smaller during this waiting period. Then, a higher dose can be safely allowed for the
reduced lesion in the next GKS session. Fig 4 presents this concept of time-staged GKS for treating
a large AVM. Yamamoto et al. used this strategy with an interval of at least 3 years between
procedures to avoid complicated dose-planning procedures. They reported that complete
obliteration occurred 3 or more years after irradiation in some patients, even on using a low dose.
The main advantage of time-staged GKS is that a suboptimal dose <1% complication line
of Kjellberg et al. can be used [
]. The suboptimal dose radiosurgery strategy induces less
hemodynamic stress by blood flow redistribution, compared with volume-staged radiosurgery
]. This might be the reason for the low complication rate in this study. The problem with
time-staged GKS is that the risk of hemorrhage still persists during the waiting period.
Yamamoto et al. reported an incidence of hemorrhage of 22.6% [
]. Although there have been
many reports about the decreased hemorrhage risk during the latency period after GKS [
], an unchanged or even increased hemorrhage risk compared with the natural course of the
disease has been reported . If an adequate dose of radiation is delivered to the entire lesion,
the risk of hemorrhage might be reduced before obliteration [
9 / 13
Fig 4. The schematic illustration of time-staged gamma knife radiosurgery (GKS) for large arteriovenous
The distinction between the concept of repeated GKS and time-staged GKS might be a
moot point. In our opinion, these procedural concepts could be distinguished by the intention
at the time of the 1st GKS session. The patients included in this study underwent time-staged
GKS, intentionally. On the other hand, repeated GKS is aimed at residual AVMs which failed
to achieve complete obliteration at the prior GKS session. There have been a few reports about
repeated GKS [29, 30]. The authors concluded that repeated GKS was relatively safe and
effective, and the prescribed dose should not be reduced for repeated radiosurgery compared to
Radiosurgery including GKS has shown favorable seizure outcomes for patients with AVM. In
a literature review, the mean seizure-free rate following radiosurgery was 53.4% (ranges,
0%95%) . The effect of radiosurgery on seizure is known to occur directly by the restriction of
epileptic activity though irradiation of gliotic capsule around the nidus, and indirectly by
reduction of blood flow by the arteriovenous shunts resulting in the ischemia in the
surrounding tissue .
Consistent with the previously published articles, the authors experienced a favorable
seizure outcome. These favorable results in terms of seizure control lead to a satisfactory
performance status and return to daily life activities. Conclusively, time-staged GKS was effective for
seizure control, and may improve the quality of life and employment status in the patients with
a large AVM.
This study has limitations as a preliminary interim report a retrospective study design. The
effect of GKS should be assessed in a large randomized cohort, with comparison to a group
receiving no treatment. The small cohort size, retrospective study design, and lack of long-term
follow-up after the final GKS session limit the power of this study.
Proper management is required for large AVMs. Time-staged GKS might be an effective and
safe treatment option in the management of large AVMs. Assessment of the long-term
10 / 13
outcome in a larger cohort is required for the validation of time-staged GKS in cases of large
S1 Table. Table A. Prognostic factors associated with AVM obliteration, Post-GKS
hemorrhage, and PRI change. Table B. Prognostic factors associated with seizure-free and seizure
Data curation: HRP JML.
Formal analysis: HRP SHP.
Funding acquisition: SHP.
Investigation: HRP SHP.
Resources: HRP JML.
Supervision: DGK SHP.
Visualization: HRP JML.
Writing – original draft: HRP.
Methodology: JWK HTC DGG SHP.
Project administration: JWK JHH HTC MHH.
Writing – review & editing: HRP JWK JHH HTC MHH DGK SHP.
11 / 13
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