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CHAPTER 13
Arteriovenous Malformation Radiosurgery:
A Twenty Year Perspective
L. Dade Lunsford, M.D., F.A.C.S., Ajay Niranjan, M.B.B.S., M.Ch.,
Douglas Kondziolka, M.D., F.A.C.S., F.R.C.S.(C.), Sait Sirin, M.D., and J.C. Flickinger, M.D.
Arteriovenous malformations (AVMs) are congenital
anomalies of the cerebrovasculature with poorly formed
blood vessels that shunt blood directly from the arterial
circulation to the venous system bypassing the capillary
network. The high pressures and flow rates in AVM vessels
combined with poor construction of the abnormal shunting
vessel walls make them prone to rupture and intracranial
hemorrhage. In some patients, they are associated with aneu-
rysms and other vascular abnormalities. The risks and bene-
fits of AVM management must be weighed carefully in each
patient. Once identified, AVMs may be suitable for one or
more of four management strategies alone or in combina-
tion:
13
observation, endovascular embolization, surgical ex-
cision, or stereotactic radiosurgery. A number of factors are
considered in making a recommendation. These factors in-
clude the patient’s age, the patient’s medical condition, bleed-
ing history, prior management, volume of AVM, location of
AVM, presenting symptoms, AVM architecture (compact
versus diffuse), “operability” estimate, presence of an aneu-
rysm, and prior experience or training. A broad management
algorithm is shown in (Figure 13.1).
Optimal management depends on the estimated risk of
subsequent hemorrhage, which is influenced by the flow and
location features as well as symptoms in each individual
patient. Younger age, prior hemorrhage, small AVM size,
deep venous drainage, and high flow may make subsequent
hemorrhage more likely. Observation may be most appropri-
ate for large-volume AVMs (average diameter 4 –5 cm),
especially for patients who have never bled.
25
Endovascular
embolization is often used as an adjunct to surgical removal
of the AVM through craniotomy and at times before stereo-
tactic radiosurgery.
38,61
Embolization before radiosurgery is
thought by some to be beneficial but may lead to less reliable
recognition of the target volume suitable for radiosurgery.
Recanalization of embolized AVM components may require
subsequent retreatment for portions of the AVM previously
thought to be occluded by successful embolization. Surgical
removal is an important option for patients with resectable
AVMs, although incomplete surgical removal may require
eventual radiosurgery. Although the size of the AVM, pattern
of venous drainage, and neurological eloquence of adjacent
brain are important considerations for prediction of outcome
after resection,
69
outcome after AVM radiosurgery can be
predicted using nidus volume and location and age of the
patient.
53
Radiosurgery is a minimal access option for pa-
tients with intracranial AVM. The chief benefit of radiosur-
gery is to eliminate the threat of spontaneous intracranial
hemorrhage by gradual obliteration of the AVM nidus over 2
to 3 years.
39,57
Initial Radiosurgical Experience
Several pioneers introduced the field of radiosurgery
for the management of brain AVMs. Raymond Kjellberg,
using the Harvard affiliated proton facility, performed Bragg
peak stereotactic radiation on more than 1000 patients with
AVM during the 1970s and early 1980s.
34,35
This technology
was designed to provide a low exit dose based on the
radiophysical characteristics of the Bragg peak. The doses
that were used were quite low relative to our current knowl-
edge of the doses needed for obliteration. Kjellberg main-
tained that the Bragg peak proton effect stabilized the AVM
blood vessels and reduced their subsequent risk of hemor-
rhage, at least in comparison to age-related survival figures
from a life insurance table. Fabrikant at the Lawrence Liver-
more Laboratory in Berkeley used the helium ion beam to
perform multisession AVM irradiation.
15
Ladislau Steiner,
working with both the first- and second-generation gamma
knife units in Stockholm, and under the guidance of the
gamma knife inventor, Lars Leksell, treated the first patient
with AVM in March 1970.
70
Using 179 highly focused
photon beams crossfired from the first-generation gamma
knife, Steiner based the target definition on biplane angiog-
raphy done during the procedure itself. This pioneering effort
set the stage for the subsequent worldwide experience using
the gamma knife technology as the number of units increased
across the world. Using linear accelerator technologies, Betti
6
in Paris and Buenos Aires, Barcia-Salorioe et al.
4,5
in Spain, and
Copyright © 2008 by The Congress of Neurological Surgeons
0148-703/08/5501-0108
Clinical Neurosurgery • Volume 55, 2008108
Columbo et al.
9–11
in Vincenza, Italy, also applied stereotactic
guidance using photon radiation generated by newer-generation
linear accelerators. These efforts were supplemented in the
United States by investigators working at the Joint Center in
Boston
40
and in Gainesville, Florida,
23
who specially modified a
linear accelerator to deliver single-session radiosurgery. Most
programs evaluated radiosurgery as an alternative to microsur-
gical removal, especially for AVMs in high-risk locations.
PITTSBURGH EXPERIENCE
At the University of Pittsburgh, the first patient with
AVM was treated in August 1987.
1
In 1991, Lunsford et al.
reported our initial experience with 227 patients who under-
went AVM radiosurgery.
42
The AVM obliteration rates at 2
years depended on nidus volume. The obliteration rates were
100% for AVMs less than 1 mL, 85% for AVMs 1 to 4 mL,
and 58% for AVMs larger than 4 mL in volume.
In the first 20 years of experience (1987–2007) in
Pittsburgh, 1100 patients with AVM underwent single or
multiple staged radiosurgery procedures. Between August
1987 and October 2004, 906 patients underwent radiosurgery
for AVMs and were eligible for 3-year follow up (Tables 13.1
and 13.2). The median patient age was 36 years (range, 3– 80
yr). Presenting symptoms included hemorrhage (46%), sei-
zures (24%), headache (18%), and neurological deficits (8%).
The AVM was detected incidentally in 4% of patients. Seven
percent of the patients had prior surgery and 21% had prior
embolization procedures. The median nidus volume was 3.4
mL (range, 0.065–57.7 mL) and the median margin dose was
20 Gy (range, 13–32 Gy). A single procedure was performed
in 865 (95.5%) patients. Prospective volume-staged radiosur-
gery was performed in 41 (4.5%) patients. Repeat radiosur-
gery for incomplete nidus obliteration after 3 years was
needed in 113 (12.5%) patients. At a median follow-up of 38
months (range, 1 to 204 months), complete nidus obliteration
was achieved in 78% (angiographic confirmation in 67% and
magnetic resonance imaging [MRI] in 33%). In addition,
20.8% of patients had achieved partial nidus obliteration. A
total of 38 hemorrhages (4.1%) occurred after radiosurgery.
Seizure control improved in 51% of those who presented with
seizures. Adverse radiation effects included new neurological
deficits in 24 patients (2.6%) and peri-AVM MRI T2 signal
increase in 108 patients (12%). Long-term complications
included cyst formation or encephalomalacia in 16 patients
(1.7%). No radiation-induced tumors were detected.
Technical Considerations
At the University of Pittsburgh, we perform intracranial
radiosurgery using the Leksell gamma knife. The selection of
patients suitable for radiosurgery is dependent on the bleed-
ing history, the age of the patient, existing comorbidities,
anatomical location, and clinical history. Patients with sus-
pected lobar AVMs receive anticonvulsants. Women of
childbearing age must have a negative pregnancy test.
After preoperative evaluations by members of the neu-
rosurgery, radiation oncology, and nursing teams, patients
report at 6:00 in the morning of the procedure day. Patients
receive intravenous conscious sedation (fentanyl and mida-
zolam) and topical and injected scalp anesthetic application at
the sites for the stereotactic frame fixation pins. Adequate
sedation followed by local pin site anesthesia is normally
sufficient within minutes and facilitates relatively painless
FIGURE 13.1. Clinical algorithm for choosing management
option for patients with intracranial AVMs.
TABLE 13.1. Patient demographics of 20-year radiosurgery
experience at the University of Pittsburgh 1987–2004
Number of patients 906
Patient age
Median 36 yr
Range 3–80 yr
Sex
Male 474 (52%)
Female 432 (48%)
Presenting symptoms
Hemorrhage 417 (46%)
Seizures 213 (24%)
Headache 164 (18%)
Sensory motor deficit 74 (8%)
Incidental 38 (4%)
Prior management
Embolization 194 (21%)
Surgery 63 (7%)
Radiosurgery
Single session 865/906 (95.5%)
Prospective volume staged 41/906 (4.5%)
Repeat radiosurgery 113/906 (12.5%)
Clinical Neurosurgery • Volume 55, 2008 Arteriovenous Malformation Radiosurgery
© 2008 The Congress of Neurological Surgeons 109
frame fixation. General anesthesia may be required for frame
application and subsequent imaging and treatment in patients
younger than 12 years of age.
As the next step, we perform stereotactic T2 fast spin
echo and contrast-enhanced three-dimensional volumetric
magnetic resonance and biplane digital subtraction angiogra-
phy in patients with AVM. MRI is contraindicated in patients
with pacemakers or other implants. In these cases we use
contrast-enhanced stereotactic computed tomography imag-
ing along with angiography.
The optimal dose range for volumetric conformal ste-
reotactic AVM radiosurgery has been largely established
based on location and volume of the AVM. Doses at the
margin of the AVM typically range from 16 to 25 Gy in a
single session, in which the volume of the AVM is defined by
stereotactic guidance during the procedure itself. The final
dose selection depends on location, volume, estimated ad-
verse radiation risks, pre-existing neurological conditions,
and bleeding history. Sharp fall-off of the radiation dose
outside of the target volume is required (maximal selectivity).
Patients usually receive a single dose (40 mg) of
methylprednisolone at the conclusion of the radiosurgery
procedure. They can continue to take their other medica-
tions (antiepileptics, analgesics, and so on) during and
after the procedure as recommended by their physicians.
Patients with AVMs in lobar subcortical locations receive
anticonvulsants.
Some patients with AVM will have been previously
treated by embolization for volumetric reduction or flow
reduction or may have had prior intracranial surgery for
hematoma evacuation or partial AVM resection. The safe
interval between surgery and stereotactic radiosurgery is not
known. It is reasonable to perform radiosurgery once the
patient has achieved a stable neurological recovery or plateau
(generally within 2 to 3 mo after the intracranial hemorrhage
or prior surgery). The optimal time between prior emboliza-
tion and radiosurgery is not known. Generally we wait for a
period of several weeks to reduce the likelihood of vascular
ischemic complications or residual cerebral edema sometimes
associated with embolization followed by early radiosurgery.
Postradiosurgical clinical examinations and MRI stud-
ies are requested at 6 months and then at annual intervals to
assess the effect of radiosurgery on AVM (gradual oblitera-
tion). If MRI at the 3-year mark suggests complete disap-
pearance of the AVM nidus, an angiogram is obtained to
confirm the obliteration (Fig. 13.2). If the MRI before 3 years
suggests nidus obliteration, angiography is generally delayed
until 3 full years have elapsed. If angiography after 3 years
demonstrates that the AVM nidus is not obliterated, repeat
stereotactic radiosurgery is recommended. Prospective ste-
reotactic radiosurgery volumetric staging is frequently per-
formed for those symptomatic patients with AVM volumes
greater than 15 cm
3
in the absence of other acceptable risk
management strategies and can be considered for AVMs
TABLE 13.2. Brain locations and radiosurgical parameters of
906 AVMs
a
AVM locations
Temporal 18.50%
Frontal 18%
Parietal 17.50%
Thalamus/basal ganglia 16%
Occipital 11.50%
Cerebellar 6.30%
Brainstem 5.50%
Dural 2.70%
Corpus callosal 2%
Intraventricular 1%
Pineal 1%
Spetzler-Martin grade
I 2.10%
II 24.40%
III 42.40%
IV 15%
V 2.70%
VI 13.4
Coexistence of aneurysm 77 (8.5%)
AVM volume
Median 3.4 mL
Range 0.065–57.7 mL
Radiosurgery dose
Median 20 Gy
Range 13–32 Gy
a
AVM, arteriovenous malformation.
FIGURE 13.2. Graph showing higher percentage of AVM
obliteration rates with higher margin doses.
Lunsford et al. Clinical Neurosurgery • Volume 55, 2008
© 2008 The Congress of Neurological Surgeons110
between 10 and 15 cm
3
. The second-stage radiosurgery is
performed at intervals between 3 and 6 months.
OUTCOME OF ARTERIOVENOUS
MALFORMATION RADIOSURGERY
The Natural History of Hemorrhage Risk
without Treatment
The overall risk of spontaneous hemorrhage from a
general brain AVM population appears to be approximately 2
to 4% per year.
49
In a large population-based 24-year study,
hemorrhage was relatively constant over the lifetime of pa-
tients with an annual risk of death of approximately 1%.
49
These risks add up to a substantial risk of hemorrhage or
death in patients with 20 or more years of an expected
lifespan. We performed an individualized analysis of the
hemorrhage risk of patients with AVM before radiosurgery.
54
The overall crude annual hemorrhage rate in this study was
2.4%. Multivariate analysis identified three factors associated
with hemorrhage risk: history of a prior bleed, identification
of a single draining vein on angiography, and a diffuse AVM
morphology on the angiogram. Four AVM hemorrhage risk
groups were constructed on the basis of these significant
factors (Table 13.3). The annual risk of initial hemorrhage
was 0.99% for low-risk AVMs with no prior hemorrhage and
no other risk factors (diffuse nidus or only one draining vein).
The annual initial hemorrhage risk was 2.22% for higher-risk
AVMs with no prior bleeds and at least one high-risk factor.
The risk of a second hemorrhage was 3.72% for AVMs with
low-risk architecture and 8.94% for those with high-risk
features (one draining vein or diffuse morphology).
The lifetime estimated bleeding risk according to pa-
tient age for initial and repeat hemorrhage from untreated
AVMs with and without high-risk features can also be cal-
culated (Table 13.4). The age at which the risk of spontane-
ous hemorrhage exceeds the risk of morbidity from radiosur-
gery depends on the location and size of the patient’s AVM.
A simple model of the estimated lifetime bleed risk is to
subtract the patient’s age from 105.
7,37
Risk of Hemorrhage after Arteriovenous
Malformation Radiosurgery
We analyzed the risk of hemorrhage during the latency
interval from radiosurgery until complete AVM oblitera-
tion.
55
We also reviewed the clinical and angiographic out-
comes of 312 patients who had a mean follow-up of 47
months. Twenty-one patients had AVM bleeds at a median of
8 months (range, 1– 60 mo) after radiosurgery. Including
three additional bleeds from untreated associated aneurysms
(5, 27, and 32 mo postradiosurgery) in two other patients with
AVM, the overall risk of postradiosurgery hemorrhage per
patient was 7.4%. The actuarial hemorrhage rate from a
patent AVM (before complete obliteration) was 4.8% per
year (95% confidence interval, 2.4 –7.0%) during the first 2
years after radiosurgery and 5% per year (95% confidence
interval, 2.3 to 7.3%) for the third to fifth years after radio-
surgery. Multivariate analysis of clinical and angiographic
factors correlated the presence of an unsecured proximal
aneurysm with an increased risk of postradiosurgical hemor-
rhage. If the AVM is immediately proximal (flow-related) to
the AVM, it will likely close as the AVM obliterates. No
AVM hemorrhages were observed after radiosurgery in seven
patients with intranidal aneurysms. We recommend that pa-
tients with AVM with aneurysms more than one arterial
branch division proximal to their AVM have their aneurysms
secured by endovascular or microsurgical approaches before
(if the aneurysm bled) or shortly after radiosurgery (espe-
cially if the aneurysm has not bled). No other factors were
correlated with the risk of hemorrhage during the latency
interval after radiosurgery. Inoue et al. identified a single
draining vein in seven with deep drainage AVMs with a
varix, four AVMs with venous obstruction and high-flow
(shunt- and mixed-type) AVMs, and large AVMs with a
volume of more than 10 mL as risk factors for hemorrhage.
29
No patient in our study had a hemorrhage after angiography,
had confirmed complete obliteration (n ⫽140), or had an
early draining vein without residual nidus (n ⫽19). In this
study, no protective benefit was conferred on patients who
had incomplete nidus obliteration in early (⬍60 mo) fol-
low-up after radiosurgery. Previous studies found no statisti-
cally significant departure from the natural hemorrhage rate at
any time period after radiosurgical treatment.
21
In a study of postradiosurgery hemorrhage, Karlsson
et al. noted that the risk for hemorrhage decreased during the
latency period.
32
In addition, these authors contended that the
risk for having a hemorrhage in the latency period after
gamma knife radiosurgery was dependent on minimum dose
delivered to the AVM nidus. Maruyama et al. in a retrospec-
tive analysis involving 500 patients who had undergone
AVM radiosurgery found that the risk of hemorrhage de-
creased by 54% during the latency period and by 88% after
obliteration.
44
These authors concluded that radiosurgery may
TABLE 13.3. Estimate lifetime risk of initial and second
hemorrhage in patients with AVM
54
a
AVM Characteristics
Risk of First
Hemorrhage
Risk of Second
Hemorrhage
Low-risk AVM (well-defined
nidus and ⬎1 draining
vein)
0.99% 3.72%
High-risk AVM (diffuse
nidus or only one draining
vein)
2.22% 8.94%
a
AVM, arteriovenous malformation.
Clinical Neurosurgery • Volume 55, 2008 Arteriovenous Malformation Radiosurgery
© 2008 The Congress of Neurological Surgeons 111
decrease the risk of hemorrhage in patients with cerebral
AVMs, even before there is angiographic evidence of oblit-
eration. This is an intriguing hypothesis that to date has defied
widespread verification. The risk of hemorrhage is further
reduced, although not eliminated, after obliteration (estimated
lifetime risk of a bleed is ⬍1%).
Probability of Arteriovenous Malformation
Obliteration with Radiosurgery
We studied the rate of AVM obliteration after gamma
knife radiosurgery at the University of Pittsburgh in 351
patients with 3 to 11 years of follow-up imaging.
19
The
median marginal dose was 20 Gy (range, 12 to 30 Gy) and
median treatment volume was 5.7 ml (range, 0.26 to 24 mL).
AVM obliteration was documented by angiography in 193 of
264 (73%) and by MRI alone and in 75 of 87 (86%) patients
who refused further angiography. Assuming a 96% accuracy
for MRI-detected obliteration, the corrected obliteration rate
for all patients was 75%.
59
In some patients with AVM
treated by radiosurgery, follow-up angiography showed evi-
dence of an early draining vein but no discernible nidus. To
our knowledge, no patient with this finding has bled, and
therefore we consider those patients obliterated or cured as well.
We identified persistent out-of-field nidus (marginal
failure) in 18% of previously embolized versus 5% of non-
embolized patients (P⫽0.006). This was the only significant
factor associated with marginal failure in univariate and
multivariate analysis. Multivariate analysis correlated in-field
obliteration with marginal dose (P⬍0.0001) and sex
(slightly lower in women [P⬍0.026] but overall obliteration
was not significantly lower [P⫽0.19]). Ellis et al. reported
26% out-of-field nidus in patients with AVM who failed
initial radiosurgery.
14
Early Adverse Effects of Radiosurgery
Adverse effects of radiosurgery include short-term
problems such as headache from the frame, nausea from pain
medication, and perhaps a small increased risk of seizure in
patients with cortical lobar AVMs, particularly if a history of
episodic seizures is present.
16,18,20,59
For this reason, we use
perioperative anticonvulsants in lobar AVMs.
Postradiosurgery Imaging Changes
Volume-related postradiosurgery imaging changes
(new areas of high T2 signal in the brain surrounding the
irradiated AVM nidus) develop in approximately 30% of
patients 1 to 24 months after radiosurgery.
16,17,20
Most such
patients (two-thirds) are asymptomatic, leaving only approx-
imately 9 to 10% of all patients developing symptomatic
postradiosurgery imaging changes (Fig. 13.3). The probabil-
ity of developing postradiosurgery imaging changes depends
on marginal dose and treatment volume. The volume of tissue
receiving 12 Gy or more (the 12-Gy volume) is the single
factor that seems to have the closest correlation with the
probability of developing imaging changes.
22
Location does
not seem to affect the risk of developing imaging changes but
has a marked effect on whether these changes are associated
with symptoms.
Symptomatic Postradiosurgery Imaging
Changes
A multi-institutional study analyzed 102 of 1255 pa-
tients with AVM who developed neurological sequelae after
radiosurgery.
16
The median marginal dose was 19 Gy (range,
10 –35 Gy) and the median treatment volume was 5.7 mL
(range, 0.26 –143 mL). The median follow-up after the onset
of complications was 34 months (range, 9 to 140 mo). Com-
TABLE 13.4. Estimate lifetime risk of hemorrhage according to history of hemorrhage and whether any high-risk morphologic
risk features (increased risk of diffuse morphology or one draining vein) are absent or present
37,54
a
Age at
Diagnosis (yr)
Expected
Lifespan (yr)
Lifetime Risk of Hemorrhage
Low-Risk AVMs High-Risk AVMs
No Prior Bleed Prior Bleed No Prior Bleed Prior Bleed
15 77 46 90.5 75.1 99.7
25 67 40.4 86.1 68.9 99.2
35 78 34.8 80.4 61.9 98.2
45 79 28.7 72.4 53.4 95.9
55 80 22 61.2 43 90.4
65 83 16.4 49.5 33.2 81.5
75 86 10.4 34.1 21.9 64.3
85 91 5.8 20.3 12.6 43
a
AVM, arteriovenous malformation.
Lunsford et al. Clinical Neurosurgery • Volume 55, 2008
© 2008 The Congress of Neurological Surgeons112
plications consisted of 80 patients with evidence of radiation-
related changes in the brain parenchyma. Seven also had
cranial nerve deficits, 12 developed seizures, and five had
delayed cyst formation. Symptom severity was classified as
minimal in 39 patients, mild in 40, disabling in 21, and fatal
in two patients. Symptoms resolved completely in 42 of 105
patients with an actuarial complete resolution rate of 54 ⫾
7% at 3 years postonset.
Permanent Sequelae of Radiosurgery
The findings from the previously mentioned study were
used to construct a model for the risk of developing perma-
nent symptomatic postradiosurgery changes. Data from 85
patients with AVM who developed symptomatic complica-
tions after gamma knife radiosurgery and 337 control patients
with no complications were evaluated as part of another
multi-institutional study.
17
After excluding patients with eas-
ily resolvable sequelae (headaches and seizures), 38 of 85
patients were classified as having permanent symptomatic
sequelae, the end point for this study. AVM marginal doses
varied from 10 to 35 Gy and treatment volumes from 0.26 to
47.9 mL. Median follow-up for patients without complica-
tions was 45 months (range, 24 to 92 months).
We constructed a multivariate model of the effects of
AVM location and the volume of tissue receiving 12 Gy or
more (12-Gy volume) for the risk of developing permanent
postradiosurgery sequelae. To rate the risk of complications
for each location, we developed a “significant postradiosur-
gery injury expression.” AVM locations in order of increas-
ing risk and significant postradiosurgery injury expression
score (from 0 to 10) were: frontal, temporal, intraventricular,
parietal, cerebellar, corpus callosum, occipital, medulla, thal-
amus, basal ganglia, and pons/midbrain. The final statistical
model predicts risks of permanent symptomatic sequelae
from significant postradiosurgery injury expression scores
and 12-Gy volumes. Table 13.5 lists the risks of permanent
symptomatic sequelae for AVMs measuring 1, 2, 3, and 4 cm
in average diameter according to location. It must be remem-
bered that this model was constructed with a limited amount
of data (38 complications) and a large number of variables
(10 different locations), so the risk predictions for some
locations (such as very small brainstem locations) are likely
overestimated. As can be seen in Table 13.2, the risks of
complications are expected to be extremely high for AVMs
that are 4 cm in average diameter in almost all locations. For
this reason, we recommend a volume-staged approach in
patients with large AVMs (15 mL or more in volume). With
volume staging, the AVM is treated in two or three 7- to
15-mL volume portions, preferably with a 5- to 6-month rest
in between portions to allow for repair of normal tissue
effects.
FIGURE 13.3. A, A dominant hemisphere AVM defined by
anteroposterior and lateral angiography at the time of radio-
surgery in 1987. B, At 3 years, complete angiographic obliter-
ation is confirmed. C, A 20-year magnetic resonance follow up
showing hyperintense signal at the obliterated AVM nidus site.
No flow void signals are seen.
Clinical Neurosurgery • Volume 55, 2008 Arteriovenous Malformation Radiosurgery
© 2008 The Congress of Neurological Surgeons 113
Late Complications after Arteriovenous
Malformation Radiosurgery
Delayed complications of radiosurgery include the risk
of hemorrhage despite angiographically documented completely
obliterated AVMs; the risk of temporary or permanent radiation
injury to the brain such as persistent edema, radiation necrosis,
and cyst formation; and the risk of radiation-induced tumors.
Cyst formation after AVM radiosurgery was first reported by
Japanese investigators who reviewed the outcomes of patients
initially treated in Sweden.
26
Delayed cyst formation has been
reported in other recent long-term follow-up studies.
30,52
In our
own 20-year experience, we have detected 16 patients (1.7%)
with delayed cyst formation. Patients who developed delayed
cyst formation were more likely to have had prior bleeds.
Various surgical approaches ranging from surgical fenestration
to cyst shunting were needed to manage these patients. Patients
with T2 signal change without additional neurological problems
generally do not need any active intervention. Chang et al.
recently suggested that hypofractionated stereotactic radiother-
apy may have a lower frequency of cyst formation than stereo-
tactic radiosurgery. However, the overall nidus obliteration rates
at 5 years were 61% for hypofractionated stereotactic radiother-
apy and 81% for stereotactic radiosurgery.
8
Of importance is the risk of radiation-induced tumors
after radiosurgery.
41
We have not detected any patient in
our more than 8500 patients who underwent gamma knife
surgery who met the criteria for a radiation-related tumor.
However, there are reports of four malignant radiation-
related tumors 5 to 10 years after radiosurgery.
31,64,65,73
It
is impossible to estimate the actual incidence of radiosur-
gery-associated cancers because the incidence (numerator)
and total number of patients who underwent radiosurgery
(denominator) are not available. However, we know that
50,000 patients had undergone gamma knife radiosurgery
by 1999 (10 years follow-up). If we estimate the gross risk
of developing a radiation-induced tumor as four in 50,000,
then one estimate is of 0.008% (one in 12,500) risk. We
warn all our patients that the risk of radiation-associated
tumor may be as high as one in 1000, although neither our
experience nor the data from Sheffield, U.K., confirms this
incidence.
63
Management of Residual Arteriovenous
Malformation after Radiosurgery
Repeat radiosurgery is the preferred option for most
patients with residual nidus remaining 3 years or more
after initial radiosurgery (Fig. 13.4). The dose–response
curve for obliterating previously treated AVM seems sim-
ilar to untreated AVM (Fig. 13.5). Permanent neurological
sequelae (but not temporary changes or imaging changes)
were slightly higher than would be expected with no prior
radiation.
43
This finding means that treating a large AVM
to a low radiation margin dose (ⱕ15 Gy) is unlikely to
achieve obliteration. The risk of late neurological sequelae
TABLE 13.5. Estimated percent risk of permanent symptomatic adverse radiation effects (radiation necrosis) for AVMs
measuring 1, 2, 3, and 4 cm in average diameter according to location
a,b
AVM Location
Risk of Symptomatic Adverse Radiation Effect
AVM Nidus Diameter
1cm 2cm 3cm 4cm
Low-risk regions
Frontal lobe 0.04 0.07 0.11 1.48
Temporal lobe 0.59 0.94 1.45 16.95
Mild-risk lesions
Intraventricular 1.32 2.11 3.22 31.63
Cerebellum 1.65 2.62 4 36.68
Parietal lobe 2.61 2.55 3.88 35.99
Moderate-risk regions
Corpus callosum 3.73 5.88 8.8 57.32
Occipital lobe 3.87 6.09 9.11 58.2
High-risk regions
Medulla 7.43 11.46 16.66 73.55
Thalamus 12.36 18.51 25.98 83
Basal ganglia 15.01 22.15 30.54 85.95
Pons/midbrain 44.02 55.89 66.19 96.46
a
AVM, arteriovenous malformation.
b
Marginal doses were chosen according to 3% guidelines from the integrated logistic formula.
16
Lunsford et al. Clinical Neurosurgery • Volume 55, 2008
© 2008 The Congress of Neurological Surgeons114
was higher after repeat radiosurgery, but the chance of
obliteration (at the same dose) was not increased by the
prior treatment. This prompted us to explore the role of
staged radiosurgery as an alternative management for
larger AVMs.
Management of Large Arteriovenous
Malformations
Large AVMs pose a challenge for surgical resection,
embolization, and radiosurgery. Some may be treated using
multimodality management, but a population of patients with
large AVMs remains “untreatable.” Although AVM emboli-
zation before radiosurgery has been used for patients with
large AVMs, recanalization was observed in 14 to 15% of
patients.
16,31
Single-stage radiosurgery of large-volume AVM
either results in unacceptable radiation-related risks attribut-
able to large volumes of normal surrounding tissue or low
obliteration efficacy. The obliteration rate after fractionated
radiotherapy (2– 4 Gy per fraction to a total dose of up to 50
Gy) is low and associated with significant side effects.
33
Kjellberg et al. used stereotactic Bragg peak proton beam
therapy for the management of large AVMs and found a
complete obliteration rate in, at best, 19% of patients.
35
However, they postulated that some protection from further
hemorrhage was achieved.
34
In a subgroup of 48 patients with
AVMs larger than 15 mL, Pan et al. found an obliteration rate
of 25% after 40 months.
51
In their single radiosurgery strat-
egy, the average margin dose was 17.7 Gy and 16.5 Gy for
AVMs with volumes 10 to 20 mL and more than 20 mL,
respectively. In their follow-up examinations, they observed
37% moderate and 12% severe adverse radiation effect in
patients with AVMs larger than 10 mL. Miyawaki et al.
reported that the obliteration rate in patients with AVMs
larger than 14 mL treated using linear accelerator radiosur-
gery was 22%.
47
Inoue et al. reported an obliteration rate of
36.4% and hemorrhage rate of 35.7% in the subgroup of
AVMs larger than 10 mL treated by radiosurgery.
29
It became
clear to us that in the narrow corridor between dose–response
and complication, the chances of achieving a high oblitera-
tion rate with a low complication rate for large AVM radio-
FIGURE 13.4. T2 signal change surrounding the target vol-
ume after radiosurgery corresponds best with the 12-Gy vol-
ume. Such changes tend to resolve by 6 to 12 months.
FIGURE 13.5. Large-volume AVMs defined by MRI and an-
giography (left) can be obliterated by performing staged ra-
diosurgery (right).
Clinical Neurosurgery • Volume 55, 2008 Arteriovenous Malformation Radiosurgery
© 2008 The Congress of Neurological Surgeons 115
surgery are slim. For this reason, radiosurgical volume stag-
ing was developed as an option to manage large AVMs.
58
Staged Volume Radiosurgery
We planned to prospectively divide the AVM nidus
into two parts if the total volume was more than 15 mL.
Usually after outlining the total volume of the AVM nidus on
the MRI, the malformation was divided into volumes (medial
or lateral, superior or inferior components) using certain
identified landmarks such as major vessel blood supply, the
ventricles, or other anatomical structures such as the internal
capsule. Using the computer dose planning system, the AVM
was divided into approximately equal volumes. Each stage
was defined at the first procedure and then recreated at
subsequent stages using internal anatomical landmarks.
These landmarks provided accurate localization at subsequent
stages because specific isodose lines could be replaced on the
same anatomical structures. The second-stage radiosurgery
procedure was performed 3 to 6 months after the first proce-
dure. Our group reported an obliteration rate of 50% (seven
of 14) after 36 months without new deficits with an additional
29% showing near total obliteration.
67
Other reports have also
documented the potential role of staged radiosurgery for large
AVMs.
62
Longer follow-up duration is needed to assess the
final outcome in these patients because some may take up to
5 years for nidus obliteration. An increased neurological
deficit was detected in only one patient and imaging showed
peri-AVM changes in four (14%) patients. In this series,
hemorrhage was observed in four (14%) patients. Although it
is difficult to document a hemorrhage rate reduction after
radiosurgery for an individual patient, we did find a reduction
in the rate of postradiosurgery bleeding in comparison with
the preradiosurgery rate. The concept of volume staging with
margin dose selection at a minimum of 16 Gy seems reason-
ably safe and effective.
Role of Preradiosurgical Embolization
Embolization may have an adjunctive role if part of the
nidus can be permanently obliterated. Preradiosurgical em-
bolization might reduce the nidus size and/or arteriovenous
shunting, which has the theoretical benefit of enhancing the
efficacy of radiosurgery because a smaller volume facilitates
a more effective higher dose. Beneficial effects of emboliza-
tions were reported in earlier studies.
45
Embolization and
radiosurgery were performed more often in our initial expe-
rience for large AVMs.
12
The purpose of embolizing large
AVMs before radiosurgery is to permanently decrease the
volume of the AVM and allow more effective radiosurgery.
Embolization can only be an effective adjunct to radiosurgery
if it results in permanent reduction of the nidus volume.
Reduction in flow within the AVM does not improve radio-
surgery results.
Our recent analysis suggested that preradiosurgical em-
bolization was a negative predictor of AVM obliteration.
56
Others have reported that in 30% of patients who had their
AVMs embolized, the nidus increased in size on the subse-
quent angiogram performed for radiosurgical targeting
46
and
12% of embolized AVMs recanalized within 1 year.
24
Re-
canalization of embolized portions of the AVM that may have
been outside the radiosurgical target results in persistent
arteriovenous shunting and treatment failure. In one series, all
patients with Spetzler-Martin Grade III to V AVMs who
underwent incomplete embolization and subsequent radiosur-
gery had incomplete obliteration.
68
Unlike surgery that re-
moves an AVM nidus within a few weeks of embolization,
radiosurgery induces AVM obliteration over 2 to 4 years.
This latency period allows sufficient time for the embolized
AVM to recanalize, remodel, or recruit new feeding arteries.
In reported series, the combination of embolization and
radiosurgery resulted in complete AVM obliteration in 47 to
55%, permanent neurological deficits in 5 to 12%, and mor-
tality in 1.5 to 2.7% of patients.
24,27,46
A recent study evalu-
ated the obliteration rate and the clinical outcomes after
radiosurgery in patients with and without previous emboliza-
tion.
2
In this study, 47 patients who had embolization and
radiosurgery were compared with 47 matching patients who
were treated with radiosurgery alone. Nidus obliteration was
achieved in 47% in the embolization group compared with
70% in the radiosurgery alone group. These data suggest that
the efficacy of combined embolization and radiosurgery is
either comparable or inferior to radiosurgery alone. The
combination of embolization and radiosurgery does not pro-
vide any additional protection against AVM hemorrhage
during the latency period with comparable risks of hemor-
rhage in treated and untreated AVMs. In short, the combina-
tion of embolization and radiosurgery does not offer any
advantages over radiosurgery alone and may have significant
disadvantages.
We have found embolization useful for patients with
dural arteriovenous fistulas (DAVF), also called dural AVMs.
DAVFs involve a vascular malformation of the wall of one of
the major venous sinuses or other dural structures.
28
The
patient presentation depends on the site and overall hemody-
namics of the lesion. Pulsatile tinnitus commonly occurs with
lesions of the transverse or sigmoid sinus
3
and may become
intolerable. With cavernous sinus lesions, double vision,
impaired vision, and exophthalmos may occur. Superior sag-
ittal sinus lesions can cause papilledema, vision loss, and
increased intracranial pressure. Cortically based lesions can
lead to hemorrhages, progressive deficits, or seizures. With
DAVFs, the overall risk of hemorrhage is approximately 2%
per year and depends on the site and hemodynamics of the
lesion.
3
The hemodynamics associated with a higher risk of
hemorrhage include cortical drainage, retrograde venous
drainage, presence of a venous varix, or drainage into the vein
Lunsford et al. Clinical Neurosurgery • Volume 55, 2008
© 2008 The Congress of Neurological Surgeons116
of Galen.
3
Dural arteriovenous fistulas with aggressive pre-
sentation require urgent evaluation and treatment. Also, pa-
tients with intractable pulsatile tinnitus, chemosis, or propto-
sis may be sufficiently affected by their symptoms to warrant
consideration of curative or at least palliative treatment.
Treatment of DAVFs has evolved over the past 3
decades. In the late 1970s and 1980s, the primary treatment
modality was surgical disconnection of the fistula and resec-
tion of the involved segment of dura and venous sinus.
3
In the
1990s, stereotactic radiosurgery followed by transarterial par-
ticulate embolization of accessible external carotid artery
feeding vessels became a primary mode of treatment at our
institution. Radiosurgery results in obliteration of DAVFs
between 1 and 3 years after treatment, analogous to the
experience with parenchymal AVMs.
36,48,50,60,66
Transarterial
embolization, usually performed the same day and a few
hours after radiosurgery, provides early palliative relief of
intractable tinnitus, orbital venous congestion, and symptoms
such as diplopia. In addition, it substantially reduces cortical
venous drainage, which may reduce the risk of hemorrhage
during the latent period after radiosurgery. Even if recanali-
zation of the embolized fistula occurs, the DAVF undergoes
simultaneous radiosurgery-induced obliteration. Emboliza-
tion is performed after radiosurgery to avoid the pitfall of
having embolization temporarily obscure portions of the
nidus that would then not be targeted during the radiosurgical
procedure. Thus, the combination of radiosurgery and
transarterial embolization, when possible, provides both rapid
symptom relief and long-term cure of DAVFs. We prefer to
perform radiosurgery first and then embolization.
With the advent of newer materials, preradiosurgery em-
bolization in the future may have a role in the management of
large AVMs. Since July 2005, Onyx 18 and Onyx 34 (Micro
Therapeutics, Inc, Irvine, CA) have been approved in the United
States by the Food and Drug Administration. Onyx is a nonad-
hesive embolic agent with lava-like flow patterns. It is possible
to interrupt the injection and analyze the actual Onyx
casting. For both of these reasons, it is possible to inject
large volumes from one catheter position in a controlled
manner and thus to embolize a large part of the AVM
without filling the draining veins or leptomeningeal col-
laterals. As a result of these properties, Onyx is thought to
produce permanent vascular occlusion.
71,72
Future Directions
AVM radiosurgery is associated with a high rate of
obliteration and low risks of complications and subsequent
hemorrhage. The chances of obliteration, permanent symp-
tomatic sequelae, and postradiosurgery hemorrhage after
radiosurgery can be predicted for individual patients ac-
cording to size, location, history, and characteristics of
their AVM. Further gains that reduce the latency interval
by accelerating the obliteration process will require inno-
vative molecular approaches. Radiation sensitizers such as
tumor necrosis factor alpha and endothelial growth factors
if delivered to the radiation volume might enhance the
effect of radiosurgery. These cytokines can be generated
on site if vectors carrying these genes are delivered into
the AVM nidus or incorporated in the embolization mate-
rial. Radiosurgery can then be performed at the appropriate
time when there is optimum expression of the therapeutic
genes from these vectors. In the future, endovascular
surgical adjuncts play a significant role in the minimally
invasive multimodal molecular management for AVMs.
This role is quite different than the current role, which is
structurally directed at immediate occlusion of selected
vessels.
Acknowledgments
Drs. Lunsford and Kondziolka are consultants with AB
Elekta. Dr. Lunsford is a stockholder.
Disclosure
The authors did not receive financial support in con-
junction with the generation of this article. The authors have
no personal or institutional financial interest in the drugs,
materials, or devices described in this article.
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Clinical Neurosurgery • Volume 55, 2008 Arteriovenous Malformation Radiosurgery
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