Results of volume-staged fractionated Gamma Knife radiosurgery for large complex arteriovenous malformations: obliteration rates and clinical outcomes of an evolving treatment paradigm

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OBJECTIVE

There are few reported series regarding volume-staged Gamma Knife radiosurgery (GKRS) for the treatment of large, complex, cerebral arteriovenous malformations (AVMs). The object of this study was to report the results of using volume-staged Gamma Knife radiosurgery for patients affected by large and complex AVMs.

METHODS

Data from 20 patients with large AVMs were prospectively included in the authors' AVM database between 2004 and 2012. A staging strategy was used when treating lesion volumes larger than 10 cm3. Hemorrhage and seizures were the presenting clinical feature for 6 (30%) and 8 (40%) patients, respectively. The median AVM volume was 15.9 cm3 (range 10.1–34.3 cm3). The mean interval between stages (± standard deviation) was 15 months (± 9 months). The median margin dose for each stage was 20 Gy (range 18–25 Gy).

RESULTS

Obliteration was confirmed in 8 (42%) patients after a mean follow-up of 45 months (range 19–87 months). A significant reduction (> 75%) of the original nidal volume was achieved in 4 (20%) patients. Engel Class I–II seizure status was reported by 75% of patients presenting with seizures (50% Engel Class I and 25% Engel Class II) after radiosurgery. After radiosurgery, 71.5% (5/7) of patients who had presented with a worsening neurological deficit reported a complete resolution or amelioration. None of the patients who presented acutely because of hemorrhage experienced a new bleeding episode during follow-up. One (5%) patient developed radionecrosis that caused sensorimotor hemisyndrome. Two (10%) patients sustained a bleeding episode after GKRS, although only 1 (5%) was symptomatic. High nidal flow rate and a time interval between stages of less than 11.7 months were factors significantly associated with AVM obliteration (p = 0.021 and p = 0.041, respectively). Patient age younger than 44 years was significantly associated with a greater than 75% reduction in AVM volume but not with AVM obliteration (p = 0.024).

CONCLUSIONS

According to the results of this study, volume-staged GKRS is an effective and safe treatment strategy for large, complex, cerebral AVMs for which microsurgery or endovascular approaches could carry substantially higher risks to the patient. Radiation doses up to 20 Gy can be safely administered. The time interval between stages should be shorter than 11.7 months to increase the chance of obliteration. High nidal flow and a patient age younger than 44 years were factors associated with nidus obliteration and significant nidus reduction, respectively.

ABBREVIATIONSAED = antiepileptic drug; AUC = area under the curve; AVM = arteriovenous malformation; DSA = digital subtraction angiography; GKRS = Gamma Knife radiosurgery; ROC = receiver operating characteristic; SM = Spetzler-Martin.

OBJECTIVE

There are few reported series regarding volume-staged Gamma Knife radiosurgery (GKRS) for the treatment of large, complex, cerebral arteriovenous malformations (AVMs). The object of this study was to report the results of using volume-staged Gamma Knife radiosurgery for patients affected by large and complex AVMs.

METHODS

Data from 20 patients with large AVMs were prospectively included in the authors' AVM database between 2004 and 2012. A staging strategy was used when treating lesion volumes larger than 10 cm3. Hemorrhage and seizures were the presenting clinical feature for 6 (30%) and 8 (40%) patients, respectively. The median AVM volume was 15.9 cm3 (range 10.1–34.3 cm3). The mean interval between stages (± standard deviation) was 15 months (± 9 months). The median margin dose for each stage was 20 Gy (range 18–25 Gy).

RESULTS

Obliteration was confirmed in 8 (42%) patients after a mean follow-up of 45 months (range 19–87 months). A significant reduction (> 75%) of the original nidal volume was achieved in 4 (20%) patients. Engel Class I–II seizure status was reported by 75% of patients presenting with seizures (50% Engel Class I and 25% Engel Class II) after radiosurgery. After radiosurgery, 71.5% (5/7) of patients who had presented with a worsening neurological deficit reported a complete resolution or amelioration. None of the patients who presented acutely because of hemorrhage experienced a new bleeding episode during follow-up. One (5%) patient developed radionecrosis that caused sensorimotor hemisyndrome. Two (10%) patients sustained a bleeding episode after GKRS, although only 1 (5%) was symptomatic. High nidal flow rate and a time interval between stages of less than 11.7 months were factors significantly associated with AVM obliteration (p = 0.021 and p = 0.041, respectively). Patient age younger than 44 years was significantly associated with a greater than 75% reduction in AVM volume but not with AVM obliteration (p = 0.024).

CONCLUSIONS

According to the results of this study, volume-staged GKRS is an effective and safe treatment strategy for large, complex, cerebral AVMs for which microsurgery or endovascular approaches could carry substantially higher risks to the patient. Radiation doses up to 20 Gy can be safely administered. The time interval between stages should be shorter than 11.7 months to increase the chance of obliteration. High nidal flow and a patient age younger than 44 years were factors associated with nidus obliteration and significant nidus reduction, respectively.

ABBREVIATIONSAED = antiepileptic drug; AUC = area under the curve; AVM = arteriovenous malformation; DSA = digital subtraction angiography; GKRS = Gamma Knife radiosurgery; ROC = receiver operating characteristic; SM = Spetzler-Martin.

The optimal treatment strategy for cerebral arteriovenous malformations (AVMs) has been a matter of debate.6,10–13,15–18,20,23,27,29–32,35 The results of a randomized study on the treatment of unruptured AVMs has substantially changed the treatment strategy for asymptomatic patients, showing a significant increase of morbidity and mortality in patients treated with medical management plus interventional therapy as compared with medical management alone.18 Large AVMs, which represent a small percentage (10%) of all AVMs, pose a formidable challenge.15 Their 5-year cumulative hemorrhage risk ranges from 5% for unruptured AVMs up to 40% for AVMs that have previously ruptured.15 Resection is associated with a risk of permanent morbidity and/or death, ranging from 12% to 40%; endovascular treatment, either transarterial or transvenous or in combination with microsurgery or stereotactic radiosurgery, has been associated with a reduced obliteration rate and an increased hemorrhage rate, although this has been debated.12,32 In addition, a recently published meta-analysis reported that Spetzler-Martin (SM) Grades III to V were independent risk factors for poor outcome after embolization.17 Theoretically, volume-staged radiosurgery could have the benefit of administering a high margin dose to the AVM nidus while maintaining a safe risk-profile. A few series report promising results using volume-staged radiosurgery for large cerebral AVMs.2,3,6,11,13,23,26,27 We think volume-staged radiosurgery should be considered the first line of treatment for these formidable cerebral vascular malformations, and here we report the results of our experience with such a treatment paradigm. Our aim was to analyze the outcome of volume-staged radiosurgery on large AVMs, and our results show how this strategy carries a significant lesion volume reduction and reasonably low complication rates.

Methods

Study Population and Treatment Algorithm

Twenty patients with large AVMs treated with volume-staged Gamma Knife radiosurgery (GKRS) between 2004 and 2012 were prospectively included in our AVM database, and the results were retrospectively evaluated. Ethics committee approval was not requested because this is a retrospective study derived from the review of a prospectively collected database. Demographics, medical history, and clinical presentation were recorded for each patient. All patients were subjected to stereotactic digital subtraction angiography (DSA) and MRI examination on the day of the programmed SRS treatment.

DSA

As part of the treatment plan, all patients underwent same-day biplanar DSA (Philips Allura FD 20/20) prior to volume-staged GKRS, with an image frame rate of 3 frames per second and injector-controlled contrast injection rates (4 cm3/sec for a total of 8 cm3). We examined angioarchitectural features on the arterial side: feeding artery enlargement (none/mild: feeding artery is the same size or only slightly more prominent than the contralateral vessel; dilated feeder: at least 1.5 times larger than the contralateral vessel), associated aneurysms, and perinidal angiogenesis as described by Valavanis and Yaşargil.31 The nidus was evaluated for volume (as determined from the original radiation plan based on cross-sectional imaging), location (eloquent vs noneloquent), nidus type (compact vs diffuse), and flow pattern (arteriovenous transit time), which was estimated by determining the number of DSA frames between the first depiction of the nidus and the first visualization of a vein (high flow: venous drainage appearing in the same frame as the AVM nidus or arterial feeders; moderate flow: 1-frame difference between visualization of the nidus and venous drainage; and low flow: venous drainage seen in > 2 frames after nidal visualization).30 For each AVM we recorded the number of venous drainages (single vs multiple), their location (deep vs superficial), and the presence or absence of venous varices/stenoses. Each DS angiogram was examined by an interventional neuroradiologist with at least 10 years of experience. We never performed superselective microcatheterization of AVM arterial feeders for SRS treatment planning.

Radiosurgery Treatment Plan

The Elekta Leksell Gamma Knife model C was used until 2007 and was later replaced by the Elekta Leksell Gamma Knife Perfexion model. Treatment plans were generated using the GammaPlan system version 10.1.1. Patients underwent stereotactic volumetric MRI, T2-weighted MRI, and cerebral DSA prior to the first volume-staged GKRS session and were then transferred to the planning station for treatment optimization. Subsequently, the total AVM volume was estimated from the dose-planning software, which allowed us to define the number of stages and staging strategy. Volume staging is usually considered for volumes greater than or equal to 10 cm3. The nidus appearance on DSA is the key element when choosing which part to treat first. Typically, the first nidal portion to appear in the DSA frames is considered to be the core, and so it is usually irradiated first. This general rule can be modified in cases of venous drainage superpositions or a deep-seated location of the nidal core. In such cases, we try to avoid irradiation of the main drainage to reduce the risk of hemorrhage prior to AVM closure. Similarly, any deep-seated nidal portions are usually irradiated after the more superficial regions to try to maximize the treatment dose while minimizing potential adverse radiation effects.23 Two plans were made upfront to try to contour the whole AVM volume. The original treatment plan strategy is then reevaluated according to follow-up imaging at the time the second fraction is performed. In subsequent sessions, MRI and DSA are repeated, and the treatment plan from the first session is coregistered to the new imaging data set to avoid dose overlap in the brain parenchyma adjacent to the AVM and to anatomically match the 2 examinations and treatment plans. We staged volume-sessions to be able to administer at least 18 Gy at the 50% isodose during each stage (number of stages: 2). The time interval between stages was 6 to 12 months. Treatment plans were defined by the treating neurosurgeon, the radiation oncologist, and the medical physicist.

Follow-Up

Neurological examination and MRI were performed for each patient every 6 months for the first 2 years and then annually. DSA was proposed to all patients after 3 years of follow-up or as soon as MRI suggested complete or near-complete AVM obliteration. Nidus obliteration was defined as follows: complete when no residual nidus was visible on DSA or on MRI for patients who refused the angiographic examination; near-complete when a reduction of more than 90% of the original nidal volume was evident by DSA or MRI follow-up; subtotal when a reduction of more than 75% of the original nidal volume was not evident by DSA or MRI follow-up; and partial when the reduction was confined to 50% or less of the original nidal volume. The complication rate was updated at each follow-up visit. Modification of prior antiepileptic drug (AED) regimens was evaluated at each outpatient visit and recorded. Follow-up DSA was performed by an interventional neuroradiologist with at least 10 years of experience and compared with the original to verify eventual changes within the treated AVM.

Statistical Analysis

Descriptive statistics are displayed as mean (± standard deviation), median, range, and percentages. Various factors that affect patient outcome were analyzed by comparing continuous variables with Mann-Whitney U-test and categorical variables with the Fisher's exact test. For continuous variables, receiver operating characteristic (ROC) curve analyses were used to assess the most predictive cutoff values through the corrected Youden index, and the discriminative power was measured by the area under the curve (AUC). The same continuous variables were then dichotomized according to the resulting cutoff, and their significance on obliteration was evaluated with the Fisher's exact test. A p value of < 0.05 was considered statistically significant.

Results

Patient Population

Between January 2004 and January 2012, 20 patients (10 male and 10 female; median age at the time of first GKRS treatment was 38 years, range 16–59 years) underwent volume-staged radiosurgery for the treatment of their cerebral AVM. Eleven (55%) patients had previously received endovascular treatment that resulted in incomplete obliteration of the AVM. The discovery of the cerebral AVM was due to neurological symptoms/signs in 17 (85%) patients, steal phenomenon causing focal neurological deficits (hemianopsia, sensorimotor deficits, mnesic deficits, gait disturbances) in 7 (35%), epileptic seizures in 8 (40%), intracerebral hemorrhage in 6 (30%), and intractable headache or unexplained dizziness/vertigo that led to diagnostic MRI evaluation in 3 (5%). In the remaining 3 (15%) patients, the cerebral AVM was incidentally discovered. Patient demographics and presentations are summarized in Table 1.

TABLE 1.

Patient demographics and clinical presenting features

VariableNo.%
Sex M/F10:1050
Age in yrs at first GKRS (range)38 (16–59)NA
Symptomatic1785
Asymptomatic315
Focal deficit/steal effect735
Epilepsy840
Hemorrhage630
Intractable headache/vertigo315
NA = not applicable.

AVM Features

Mean and median AVM volume were 15.9 and 13.2 cm3, respectively (range 10.1–34.3 cm3). Nineteen (95%) patients had AVMs located in the supratentorial region. The AVM was located in the frontal lobe in 3 (15%) patients, the temporal lobe in 2 (10%) patients, and the occipital lobe in 1 (5%) patient. Twelve (60%) AVMs were large enough to invade more than a single cerebral lobe. The thalamus, callosal body, and adjacent ventricular structures were involved in 1 (5%) patient each. Fifteen (75%) AVMs affected eloquent portions of the cerebral cortex. Cerebral AVMs were further evaluated according to the SM classification system.28 Ten (50%) AVMs were classified as SM Grade III, 7 (35%) as SM Grade IV, and 3 (6%) as SM Grade V. AVM characteristics are outlined in Table 2.

TABLE 2.

Summary of AVM features

VariableNo. (range)%
Median vol of AVM in cm315.9 (10.1–34.3)NA
Lobe
  Temporal210
  Frontal315
  Occipital15
Posterior fossa15
Thalamic15
Diffuse1260
Eloquent1575
Prior embolization1155
Interval btwn stages in mos13 (8–32)
SM grade
  III1050
  IV735
  V315
Pollock-Flickinger scale score
  >21680
  1.5–2420
  1–1.500

A total of 16 (85%) AVMs scored > 2 on the Pollock-Flickinger scale;21 the remaining 4 (15%) scored between 1.51 and 2.00. Angioarchitectural features are outlined in Table 3. A high flow rate was detected by angiography in 13 (70%) patients, moderate flow rate in 5 (25%), and low flow rate in 1 (5%). Nidal morphology was considered to be compact in 3 (15%) patients, while the vast majority (17/20; 85%) displayed features suggestive of perinidal neoangiogenesis associated with a diffuse nidal angiographic pattern. All direct feeders evaluated via selective catheterization were dilated; feeders were present in a superficial (i.e., cortical) territory in 10 (50%) patients, a deep location in 1 (5%), and in a mixed superficial and deep location in 9 (45%). Venous drainage was deep seated in 3 (15%) patients, superficial in 6 (30%), and mixed in 11 (55%). Single drainage was detected in 7 (37%) patients, while the majority (12; 63%) showed multiple, dilated, venous drainages. Venous varices were noted in 4 (20%) patients, while venous stenosis was only detected in 1 (5%) patient. Five (20%) patients presented with flow-related aneurysmal malformations on 1 of the afferent nidal arteries. Ten (50%) of the treated AVMs showed surrounding parenchymal edema at the baseline MRI study.

TABLE 3.

AVM angioarchitecture

VariableNo.%
Flow
  High1369
  Moderate526
  Low15
Drainage
  Superficial630
  Deep315
  Mixed1155
Drainage
  Single737
  Multiple1263
Nidus
  Compact315
  Diffuse*1785
Venous dilation/aneurysms
  Present424
  Absent1376
Venous stenosis
  Present15
  Absent1995
Feeders location
  Deep15
  Mixed945
  Superficial1050
Feeders dilation
  Yes20100
  No00

With associated features of perinidal angiogenesis

Gamma Knife Treatment

The median total AVM volume was 15.9 cm3 (mean 13.2 cm3, range 10.1–34.3 cm3). AVMs were treated with 2 fractions of GKRS, with a mean interval between fractions of 15 ± 6 months. The mean target volume was 8.00 ± 3.78 cm3 for the first fraction and 5.00 ± 2.19 cm3 for the second fraction; the mean prescription dose was 20 ± 2 Gy at the 50% isodose, with 96% and 97% volume coverage during the first and second session, respectively. Treatment variables are presented in Table 4.

TABLE 4.

GKRS features*

ParameterVol-Staged GKRS
1st Stage2nd Stage
Target vol (cm3)7.8 (2.7–15.8)4.7 (0.8–10.6)
Margin dose (Gy)20 (18–25)20 (13–24)
Max dose (Gy)40 (36–50)41 (26–49)
No. of isocenters17 (5–26)13 (4–24)
V12 (cm3)24.3 (14.3–42.7)15.5 (0.2–32.6)
V10 (cm3)32.1 (18.7–55.5)21.6 (0.4–41.8)
% coverage96 (90–100)97 (91–100)
V10 = volume receiving 10 Gy; V12 = volume receiving 12 Gy.

Values are presented as the median (range).

Obliteration Rates

Thirteen (68%) patients underwent DSA at last follow-up (Table 5). The remaining 6 (32%) refused DSA and were evaluated by MRI. One patient was lost to followup. Obliteration of the AVM nidus was confirmed in 8/19 (42%) patients. Four (21%) patients had an AVM volume reduction of more than 75% at last angiographic follow-up, while the same proportion (21%) showed a 50% volume reduction. In 3 (16%) patients, the AVM volume was unchanged after 2 SRS sessions. On univariate analysis, high nidal flow and a shorter interval between radiosurgical sessions (less than 11 months as a dichotomized variable) were significantly associated with higher obliteration rates at last follow-up (p = 0.021 and p = 0.041, respectively; Table 6). Other angioarchitectural variables, pre-GKRS embolization, hemorrhage, patient age, or AVM volume were not statistically associated with GKRS outcome at followup. Younger patient age (≤ 44 years) was significantly associated with a strong response to radiosurgical treatment (> 75% reduction in nidal volume; p = 0.024) but was not associated with AVM obliteration at last follow-up.

TABLE 5.

Patient outcomes and follow-up

VariableNo.%
Median follow-up in mos. (range)45 (19–87)NA
DSA at follow-up1368
MRI at follow-up632
Total obliteration842
>75% occlusion420
50% occlusion420
AVM vol unchanged315
Hemorrhage210
Seizures
  Completely resolved (Engel Class I)450
  Ameliorated (Engel Class II)225
  Stable112.5
Neurological deficit
  Completely recovered228.5
  Improved343
  Unchanged228.5
Complications
  Hemisyndrome15.2
  Radionecrosis15.2
  Hemorrhage210.5
  Symptomatic hemorrhage15.2
TABLE 6.

Statistical analyses

FactorOutcome
AVM ObliterationAVM Reduction >75%
Nidal flowp = 0.021
Age≤44 yrs (AUC = 0.76); p = 0.024
Time btwn GKRS fractions≤11.7 mos (AUC = 0.72); p = 0.041

Clinical Follow-Up After Volume-Staged Radiosurgery

Clinical follow-up was available for 19 patients (1 was lost to follow-up). Four (50%) of 8 patients reported a complete disappearance of epileptic seizures, allowing them to stop AEDs. Two (25%) of 8 reported a reduction in seizure frequency, while the same proportion (1/8; 12.5%) reported no change in both frequency and intensity of epileptic discharges. Among the 6 patients who presented acutely due to intracerebral bleeding, none experienced a rebleeding episode during the follow-up period. Of the 7 patients who presented with focal neurological deficits, 2 (28.5%) experienced a complete recovery, 3 (43%) reported improvement, and 2 (28.5%) reported no change. Regarding adverse events during follow-up, 1 (5.2%) patient developed radionecrosis partially affecting the cortical motor area, which caused contralateral hemicorporeal motor deficit; this patient is still slowly recovering after more than 1 year of physiotherapy kinesiotherapy. Intracerebral hemorrhages were detected in 2 (10.5%) patients during follow-up, and in 1 patient the bleeding episode was severe enough to cause a focal deficit (namely, homonymous hemianopia). Both bleeding episodes were managed conservatively. New epileptic seizures developed in 2 (10.5%) patients, and both frequency and intensity of epileptic episodes were controlled by AEDs. Sporadic paresthesias and tinnitus-like auditory disturbances occurred in 1 (5.3%) patient each. Clinical follow-up is reported in Table 5. Table 7 shows patients' clinical history and GKRS details/outcome data.

TABLE 7.

Patients' clinical history and GKRS details/outcome

Sex of PatientAge at 1st GKRS (yrs)Clinical PresentationAVM Vol (cm3)Prior EmbolizationSM GradePF ScoreMean Dose at 50% IsodoseOutcomePost-GKRS ComplicationsPost-GKRS SeizuresPost-GKRS DeficitFU (after 2nd GKRS)
M24Intractable headache11.48No41.6415.550% occlusion19
F16Hemorrhage, lt hemiplegia12.7Yes42.0918Total obliterationUnchanged38
M55Hemorrhage, rt hemianopsia14.11Yes42.521.5>75% occlusionImproved19
M23Epilepsy24.3No32.8820Total obliterationAmeliorated (Engel Class II)87
M59Epilepsy34.2No54.620AVM vol unchangedHemorrhageStable43
F46Hemorrhage, vertigo, amnestic disorders12.05Yes32.1424Total obliterationImproved34
F39Incidental finding10.1Yes31.7820>75% occlusion44
F51Hemorrhage, amnestic disorders16.7Yes52.692050% occlusionCompletely resolved36
M18Epilepsy, sensorimotor deficit lt leg15.9No31.9419Total obliterationCompletely resolved (Engel Class I)Improved51
F53Epilepsy13.2No32.3920Total obliterationCompletely resolved (Engel Class I)46
F26Hemorrhage10.48Yes42.0720Total obliteration54
M40Epilepsy15.9Yes42.3820Total obliterationCompletely resolved (Engel Class I)42
F56Vertigo12.6Yes32.3822AVM vol unchanged52
F44Epilepsy12.3Yes42.1120>75% occlusionHemisyndrome due to radionecrosisAmeliorated (Engel Class II)31
M46Partial CN III deficit10.7No31.9920AVM vol unchangedCompletely resolved52
M22Hemianopsia26.3Yes53.082050% occlusionSymptomatic hemorrhageUnchanged64
M27Hemorrhage16.52No32.1823.5>75% occlusion56
M35Incidental finding23.4Yes33.0422Total obliteration35
F46Epilepsy11.8No42.092050% occlusionCompletely resolved (Engel Class I)50
F27Epilepsy14.7Yes32.0021Lost at FU
CN = cranial nerve; FU = follow-up; PF = Pollock-Flickinger scale.

Discussion

The management of large AVMs is a formidable challenge. Hypofractionated stereotactic radiotherapy has been described as an adjunctive strategy for reducing giant (e.g., > 5 cm) AVMs, making them amenable to single-dose radiosurgery.34 Staged GKRS has been described as an effective strategy for the management of these dreadful vascular lesions. A recent systematic review on the subject suggested that volume-staging is a potentially superior approach to dose-staging for GKRS, based on higher obliteration rates and similar complication rates.19 A few studies have shown promising results in terms of obliteration rates and adverse events following volume-staged SRS for large cerebral AVMs. Our obliteration rate of 42% is in line with results previously reported by others,2,3,6,11,13,23,26,27 which range from 10% to 62% for series describing more than 10 patients. A significant proportion of our patients had a nidus characterized by diffuse morphology and features of perinidal angiogenesis and high nidal flow; these features are associated with a lower rate of postradiosurgical obliteration.20,30,35 Interestingly, Paúl et al. recently published the largest series to date evaluating angiographic predictors of AVM obliteration. In that study, the authors acknowledged the presence of a higher obliteration rate for high-flow AVMs; a high flow rate can decrease the obliteration rate only within a given volume—i.e., for two AVMs with the same volume, there is a greater chance for obliteration in the low-flow AVM.20 In our reported population of large, complex AVMs, high flow was found to be an angiographic predictor of AVM obliteration on follow-up. Considering the dynamic process of radiosurgical treatment for large, cerebral AVMs, it is reasonable to expect even higher obliteration rates with longer follow-up. This has been clearly shown by Huang et al.11 and Kano et al.13 in 2012: in both papers the authors used Kaplan-Meier curves to show a progressive increase in the total obliteration rate over time. In particular, Huang et al. showed a 29% obliteration rate by 5 years and up to 89% at 10 years. However, in our univariate analysis there was no correlation between time and obliteration, probably because of the small number of patients. Interestingly, MRI suggested complete AVM obliteration in 2 patients whose angiographic control showed the persistence of a single, small draining vein without the presence of a nidus-like pattern. This particular feature has been found several other times in our experience (unpublished data), and we think it represents the last remaining part of the microvascular shunt. We classified those patients within the complete obliteration subgroup, and we scheduled a follow-up DSA after 12 months. (Figure 1 shows an example of a persistent single draining vein, and Fig. 2 shows a complete response.) The management of patients who show residual AVM filling volume at last follow-up is challenging and currently debated. Many options are theoretically available within the armamentarium of the treating neurosurgeon. Resection of an AVM previously reduced by GKRS can be an effective option, as reported by Seymour et al.26 Repeating a radiosurgical procedure can also be an effective option, so long as it is technically feasible according to the previously irradiated volumes and dosimetry plan, and adverse event risks are carefully weighed.

FIG. 1.
FIG. 1.

Patient who responded to GKRS with extreme reduction of the AVM. A: Pretreatment DS angiogram (first fraction) showing the malformation nidus. B: Treatment planning on MRI (first fraction) showing the malformation nidus and the GKRS treatment (50% of the isodose outlined in yellow). C: Treatment planning on MRI (second fraction) showing the malformation nidus and the GKRS treatment (50% of the isodose outlined in yellow). D: Follow-up DS angiogram at 46 months after the first fraction treatment, showing complete obliteration of the AVM nidus and only an early vein draining into the superior sagittal sinus, filled by the contrast medium during the arterial phase (white arrow).

FIG. 2.
FIG. 2.

Patient who responded to GKRS with complete obliteration of the AVM. A: Pretreatment DS angiogram (first fraction) showing the malformation nidus. B: Treatment planning on MRI (first fraction) showing the malformation nidus and the GKRS treatment (50% of the isodose outlined in yellow). C: Treatment planning on MRI (second fraction) showing the malformation nidus and the GKRS treatment (50% of the isodose outlined in yellow). D: Complete obliteration of the AVM, as seen on follow-up DS angiogram, at 61 months after the first fraction treatment.

In our institution, the treatment choice is routinely made on a case-by-case basis according to benefits and risks related to volume, location, potential surgical morbidity, angiographic features such as the presence of related aneurysms, and the patient's choice. Patients who are not amenable to or who refused post-GKRS treatment are monitored by annual follow-up. Hemorrhage prevention is a key element in cerebral AVM treatment, and the risk of rupture or rehemorrhage of a previously ruptured AVM theoretically remains until its obliteration; this has long been mentioned as a “weakness” of radiosurgical treatment. This is particularly true when dealing with large AVMs. Large nidus size, diffuse nidus on angiography, and previous hemorrhages have all been reported as risk factors for rupture/rerupture by several experienced groups.1,8–10,22,28 In previously reported series of volume-staged GKRS treatment for AVMs, the postradiosurgical hemorrhage rate ranged from 14.2% up to 27.7%.2,3,6,11,13,23,26,27 In addition, Huang et al.11, Sirin et al.31, and Kano et al.13 detailed neurological outcomes for patients who suffered a post-radiosurgical bleeding episode: 8/19 (42%) deaths were reported overall. In our series, none of the patients who presented acutely with intracerebral hemorrhage experienced a rebleeding episode, and we discovered only 2 (10%) patients who suffered from a bleeding episode after radiosurgery. In our experience, both episodes were neurologically mild without leaving permanent incapacitating deficits. A higher margin dose, a careful analysis of the pretreatment DSA, and shielding of the venous drainage while defining the plan could be factors related to the low hemorrhage rate reported in our series. Hemorrhage characteristics (e.g., significant subarachnoid hemorrhage or pure intraventricular bleeding when choroidal feeders are involved by the AVM nidus) should prompt aggressive diagnostics, such as superselective microcatheterization, and treatment of eventual ruptured associated aneurysms. Neurological deficits secondary to hemodynamic/steal effects or seizures can be severe enough to incapacitate patients' lives, especially considering the dramatic effect that large AVMs can exert on the cerebral circulation. Considering the inherent difficulty of achieving a complete obliteration for such challenging lesions, seizure control and prevention of neurological deficit progression are key objectives in the radiosurgical treatment of large AVMs. The dramatic positive effect of radiosurgical treatment on seizure outcome has been previously reported to be up to 80%4,7,24,33 and related to obliteration. This also holds true for large cerebral AVMs, as we reported 50% of patients to be seizure-free (Engel Class I) and 25% to have a significant reduction in epileptic episodes (Engel Class II), thereby achieving an overall good outcome in seizure control for 75%. We did find a significant amelioration of neurological deficits in the reported population; in particular, 5/7 (71.4%) patients who presented with neurological deficits due to AVM hemodynamics/steal phenomenon experienced a resolution (2/7; 28.5%) or improvement (3/7; 42.8%) in their neurological signs/symptoms. Neither the length of follow-up nor AVM obliteration was statistically associated with this neurological improvement, although we attributed the beneficial effects to modifications in AVM hemodynamics, leading to a reduced steal effect on the cerebral circulation.25 Adverse effects of radiation traditionally represented a key problem in the radiosurgical management of large cerebral AVMs. Adverse radiation effects have been associated with a large nidus and a higher margin dose, among other factors.5,14 Historically, the volume-staging strategy emerged to enable the administration of a higher global dose to a large volume while maintaining a low rate of adverse effects.23 With the exception of Dalyai et al.6, we administered a higher margin dose than the vast majority of reported series for volume-staged fractionation of large cerebral AVMs (20 Gy at the 50% isodose), and we used a longer time interval between stages. The long mean interval between sessions (15 ± 6 months) is explained by 4 patients who initially refused the second treatment and later accepted it. According to our results, high doses in the reported range are safe and feasible, even when treating large AVMs, as evidenced by the low overall rate (2/19, 10.5%) of adverse radiation effects in the present series, with only 1 (5%) patient who experienced a new persistent neurological deficit. This compares positively with the reported range of adverse effects or complications (11.2%–14%) in other series of volume-staged radiosurgery.2,3,6,11,13,23,26,27 On the contrary, we are currently modifying our treatment algorithm to shorten the time interval between stages so it is in greater alignment with that reported by others.2,3,6,11,13,23,26,27 Fifty-five percent of the reported population had been subjected to endovascular embolization prior to volume-staged radiosurgery. This has been reported to be potentially associated with reduced obliteration rates, likely due to more difficult nidus targeting and hemodynamic effects rather than volume-decreasing ones. We did not find any statistically significant association between prior embolization and obliteration rate. This has been previously shown in literature; in particular, Huang et al. presented the longest follow-up available11 and reported similar cumulative closure rates for the 2 groups (embolized vs not embolized). Total AVM volume per se has been reported both to be and not to be strongly related to obliteration rate. In the series presented by Kano et al., “small” AVM volume was associated with increased obliteration rates in univariate analysis only, without being confirmed in multivariate analysis.13 On the contrary, Seymour et al. found AVM volume to be predictive of AVM obliteration in multivariate analysis.26 Even though our results are weakened by the inherent limitations associated with low patient numbers, AVM volume was not found to be predictive of total obliteration; this finding is probably due to similar AVM volumes among the majority of our reported population, making it difficult to stratify volume in such a way as to infer a statistically significant effect. Our study has several limitations. First, single-center studies can be subject to selection bias. Second, the low number of patients prevents us from being able to generalize our results. The relative shortness of our follow-up period (45 months [range 19–87 months]) may have led us to an underestimation of adverse effects, e.g., delayed cyst formation. Our patient follow-up will continue for at least 5 years after AVM obliteration. Still, it is our belief that the results presented here can add valuable data to the available literature concerning this promising treatment strategy.

Conclusions

A high margin dose can be administered with a safe profile of adverse effects and be effective in obliterating or at least significantly reducing large, complex, cerebral AVMs. Volume-staged SRS can dramatically ameliorate the clinical picture for these patients for whom there are often only few, if any, other therapeutic options. In conclusion, good obliteration rates, a significant impact on seizures, and reduced neurological deficits with an acceptable rate of complications are the key elements that make volume-staged radiosurgery the first-line treatment strategy for complex, large, cerebral AVMs.

References

  • 1

    Abecassis IJXu DSBatjer HHBendok BR: Natural history of brain arteriovenous malformations: a systematic review. Neurosurg Focus 37:3E72014

    • Search Google Scholar
    • Export Citation
  • 2

    AlKhalili KChalouhi NTjoumakaris SRosenwasser RJabbour P: Staged-volume radiosurgery for large arteriovenous malformations: a review. Neurosurg Focus 37:3E202014

    • Search Google Scholar
    • Export Citation
  • 3

    Back AGVollmer DZeck OShkedy CShedden PM: Retrospective analysis of unstaged and staged Gamma Knife surgery with and without preceding embolization for the treatment of arteriovenous malformations. J Neurosurg 109:Suppl57642008

    • Search Google Scholar
    • Export Citation
  • 4

    Baranoski JFGrant RAHirsch LJVisintainer PGerrard JLGünel M: Seizure control for intracranial arteriovenous malformations is directly related to treatment modality: a meta-analysis.. J Neurointerv Surg 6:6846902014

    • Search Google Scholar
    • Export Citation
  • 5

    Cohen-Inbar OLee CCXu ZSchlesinger DSheehan JP: A quantitative analysis of adverse radiation effects following Gamma Knife radiosurgery for arteriovenous malformations. J Neurosurg 123:9459532015

    • Search Google Scholar
    • Export Citation
  • 6

    Dalyai RTheofanis TStarke RMChalouhi NGhobrial GJabbour P: Stereotactic radiosurgery with neoadjuvant embolization of larger arteriovenous malformations: an institutional experience. BioMed Res Int 2014:3065182014

    • Search Google Scholar
    • Export Citation
  • 7

    Ditty BJOmar NBForeman PMMiller JHKicielinski KPFisher WS III: Seizure outcomes after stereotactic radiosurgery for the treatment of cerebral arteriovenous malformations.. J Neurosurg [epub ahead of print]2016

    • Search Google Scholar
    • Export Citation
  • 8

    Flores BCKlinger DRRickert KLBarnett SLWelch BGWhite JA: Management of intracranial aneurysms associated with arteriovenous malformations. Neurosurg Focus 37:3E112014

    • Search Google Scholar
    • Export Citation
  • 9

    Fults DKelly DL Jr: Natural history of arteriovenous malformations of the brain: a clinical study. Neurosurgery 15:6586621984

  • 10

    Hernesniemi JADashti RJuvela SVäärt KNiemelä MLaakso A: Natural history of brain arteriovenous malformations: a long-term follow-up study of risk of hemorrhage in 238 patients. Neurosurgery 63:8238312008

    • Search Google Scholar
    • Export Citation
  • 11

    Huang PPRush SCDonahue BNarayana ABecske TNelson PK: Long-term outcomes after staged-volume stereotactic radiosurgery for large arteriovenous malformations. Neurosurgery 71:6326442012

    • Search Google Scholar
    • Export Citation
  • 12

    Iosif CMendes GASaleme SPonomarjova SSilveira EPCaire F: Endovascular transvenous cure for ruptured brain arteriovenous malformations in complex cases with high Spetzler-Martin grades. J Neurosurg 122:122912382015

    • Search Google Scholar
    • Export Citation
  • 13

    Kano HKondziolka DFlickinger JCPark KJParry PVYang HC: Stereotactic radiosurgery for arteriovenous malformations, Part 6: multistaged volumetric management of large arteriovenous malformations. J Neurosurg 116:54652012

    • Search Google Scholar
    • Export Citation
  • 14

    Kano HKondziolka DFlickinger JCYang HCFlannery TJAwan NR: Stereotactic radiosurgery for arteriovenous malformations, Part 3: outcome predictors and risks after repeat radiosurgery. J Neurosurg 116:21322012

    • Search Google Scholar
    • Export Citation
  • 15

    Laakso ADashti RJuvela SIsarakul PNiemelä MHernesniemi J: Risk of hemorrhage in patients with untreated Spetzler-Martin grade IV and V arteriovenous malformations: a long-term follow-up study in 63 patients. Neurosurgery 68:3723782011

    • Search Google Scholar
    • Export Citation
  • 16

    Lawton MT: Seven AVMs: Tenets and Techniques for Resection. New YorkThieme2014. 313317

  • 17

    Ledezma CJHoh BLCarter BSPryor JCPutman CMOgilvy CS: Complications of cerebral arteriovenous malformation embolization: multivariate analysis of predictive factors. Neurosurgery 58:6026112006

    • Search Google Scholar
    • Export Citation
  • 18

    Mohr JPParides MKStapf CMoquete EMoy CSOverbey JR: Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 383:6146212014

    • Search Google Scholar
    • Export Citation
  • 19

    Moosa SChen CJDing DLee CCChivukula SStarke RM: Volume-staged versus dose-staged radiosurgery outcomes for large intracranial arteriovenous malformations. Neurosurg Focus 37:3E182014

    • Search Google Scholar
    • Export Citation
  • 20

    Paúl LCasasco AKusak MEMartinez NRey GMartinez R: Results for a series of 697 arteriovenous malformations treated by Gamma Knife: influence of angiographic features on the obliteration rate.. Neurosurgery 75:568563583:2014

    • Search Google Scholar
    • Export Citation
  • 21

    Pollock BEFlickinger JC: A proposed radiosurgery-based grading system for arteriovenous malformations. J Neurosurg 96:79852002

  • 22

    Pollock BEFlickinger JCLunsford LDBissonette DJKondziolka D: Factors that predict the bleeding risk of cerebral arteriovenous malformations. Stroke 27:161996

    • Search Google Scholar
    • Export Citation
  • 23

    Pollock BEKline RWStafford SLFoote RLSchomberg PJ: The rationale and technique of staged-volume arteriovenous malformation radiosurgery. Int J Radiat Oncol Biol Phys 48:8178242000

    • Search Google Scholar
    • Export Citation
  • 24

    Schäuble BCascino GDPollock BEGorman DAWeigand SCohen-Gadol AA: Seizure outcomes after stereotactic radiosurgery for cerebral arteriovenous malformations. Neurology 63:6836872004

    • Search Google Scholar
    • Export Citation
  • 25

    Schuster LSchenk EGiesel FHauser TGerigk LZabel-Du-Bois A: Changes in AVM angio-architecture and hemodynamics after stereotactic radiosurgery assessed by dynamic MRA and phase contrast flow assessments: a prospective follow-up study. Eur Radiol 21:126712762011

    • Search Google Scholar
    • Export Citation
  • 26

    Seymour ZASneed PKGupta NLawton MTMolinaro AMYoung W: Volume-staged radiosurgery for large arteriovenous malformations: an evolving paradigm. J Neurosurg 124:1631742016

    • Search Google Scholar
    • Export Citation
  • 27

    Sirin SKondziolka DNiranjan AFlickinger JCMaitz AHLunsford LD: Prospective staged volume radiosurgery for large arteriovenous malformations: indications and outcomes in otherwise untreatable patients. Neurosurgery 62:Suppl 27447542008

    • Search Google Scholar
    • Export Citation
  • 28

    Spetzler RFMartin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:4764831986

  • 29

    Stefani MAPorter PJterBrugge KGMontanera WWillinsky RAWallace MC: Large and deep brain arteriovenous malformations are associated with risk of future hemorrhage. Stroke 33:122012242002

    • Search Google Scholar
    • Export Citation
  • 30

    Taeshineetanakul PKrings TGeibprasert SMenezes RAgid RterBrugge KG: Angioarchitecture determines obliteration rate after radiosurgery in brain arteriovenous malformations. Neurosurgery 71:107110792012

    • Search Google Scholar
    • Export Citation
  • 31

    Valavanis AYaşargil MG: The endovascular treatment of brain arteriovenous malformations. Adv Tech Stand Neurosurg 24:1312141998

  • 32

    van Beijnum Jvan der Worp HBBuis DRAl-Shahi Salman RKappelle LJRinkel GJ: Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA 306:201120192011

    • Search Google Scholar
    • Export Citation
  • 33

    Walczak T: Surgical Treatment of the Epilepsies ed 2New YorkRaven Press1994

  • 34

    Xiao FGorgulho AALin CSChen CHAgazaryan NViñuela F: Treatment of giant cerebral arteriovenous mal formation: hypofractionated stereotactic radiation as the first stage. Neurosurgery 67:125312592010

    • Search Google Scholar
    • Export Citation
  • 35

    Zipfel GJBradshaw PBova FJFriedman WA: Do the morphological characteristics of arteriovenous malformations affect the results of radiosurgery?. J Neurosurg 101:3934012004

    • Search Google Scholar
    • Export Citation

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Franzin, Panni, Spatola, Mortini. Acquisition of data: Panni, Spatola, Gigliotti, Donofrio. Analysis and interpretation of data: Panni, del Vecchio, Gallotti, Gigliotti, Cavalli. Drafting the article: Franzin, Panni, Spatola, del Vecchio, Gallotti. Critically revising the article: Franzin, Panni, del Vecchio, Cavalli, Mortini. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Franzin. Statistical analysis: Gallotti, Gigliotti.

Supplemental Information

Previous Presentations

A portion of this study was presented at the Leksell Gamma Knife Society 2016 meeting, Amsterdam, the Netherlands, May 18, 2016.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Contributor Notes

INCLUDE WHEN CITING DOI: 10.3171/2016.7.GKS161549.Correspondence Alberto Franzin, Department of Neurosurgery and Radiosurgery, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, Milan 20132, Italy. email: franzin.alberto@hsr.it.
Headings
Figures
  • View in gallery

    Patient who responded to GKRS with extreme reduction of the AVM. A: Pretreatment DS angiogram (first fraction) showing the malformation nidus. B: Treatment planning on MRI (first fraction) showing the malformation nidus and the GKRS treatment (50% of the isodose outlined in yellow). C: Treatment planning on MRI (second fraction) showing the malformation nidus and the GKRS treatment (50% of the isodose outlined in yellow). D: Follow-up DS angiogram at 46 months after the first fraction treatment, showing complete obliteration of the AVM nidus and only an early vein draining into the superior sagittal sinus, filled by the contrast medium during the arterial phase (white arrow).

  • View in gallery

    Patient who responded to GKRS with complete obliteration of the AVM. A: Pretreatment DS angiogram (first fraction) showing the malformation nidus. B: Treatment planning on MRI (first fraction) showing the malformation nidus and the GKRS treatment (50% of the isodose outlined in yellow). C: Treatment planning on MRI (second fraction) showing the malformation nidus and the GKRS treatment (50% of the isodose outlined in yellow). D: Complete obliteration of the AVM, as seen on follow-up DS angiogram, at 61 months after the first fraction treatment.

References
  • 1

    Abecassis IJXu DSBatjer HHBendok BR: Natural history of brain arteriovenous malformations: a systematic review. Neurosurg Focus 37:3E72014

    • Search Google Scholar
    • Export Citation
  • 2

    AlKhalili KChalouhi NTjoumakaris SRosenwasser RJabbour P: Staged-volume radiosurgery for large arteriovenous malformations: a review. Neurosurg Focus 37:3E202014

    • Search Google Scholar
    • Export Citation
  • 3

    Back AGVollmer DZeck OShkedy CShedden PM: Retrospective analysis of unstaged and staged Gamma Knife surgery with and without preceding embolization for the treatment of arteriovenous malformations. J Neurosurg 109:Suppl57642008

    • Search Google Scholar
    • Export Citation
  • 4

    Baranoski JFGrant RAHirsch LJVisintainer PGerrard JLGünel M: Seizure control for intracranial arteriovenous malformations is directly related to treatment modality: a meta-analysis.. J Neurointerv Surg 6:6846902014

    • Search Google Scholar
    • Export Citation
  • 5

    Cohen-Inbar OLee CCXu ZSchlesinger DSheehan JP: A quantitative analysis of adverse radiation effects following Gamma Knife radiosurgery for arteriovenous malformations. J Neurosurg 123:9459532015

    • Search Google Scholar
    • Export Citation
  • 6

    Dalyai RTheofanis TStarke RMChalouhi NGhobrial GJabbour P: Stereotactic radiosurgery with neoadjuvant embolization of larger arteriovenous malformations: an institutional experience. BioMed Res Int 2014:3065182014

    • Search Google Scholar
    • Export Citation
  • 7

    Ditty BJOmar NBForeman PMMiller JHKicielinski KPFisher WS III: Seizure outcomes after stereotactic radiosurgery for the treatment of cerebral arteriovenous malformations.. J Neurosurg [epub ahead of print]2016

    • Search Google Scholar
    • Export Citation
  • 8

    Flores BCKlinger DRRickert KLBarnett SLWelch BGWhite JA: Management of intracranial aneurysms associated with arteriovenous malformations. Neurosurg Focus 37:3E112014

    • Search Google Scholar
    • Export Citation
  • 9

    Fults DKelly DL Jr: Natural history of arteriovenous malformations of the brain: a clinical study. Neurosurgery 15:6586621984

  • 10

    Hernesniemi JADashti RJuvela SVäärt KNiemelä MLaakso A: Natural history of brain arteriovenous malformations: a long-term follow-up study of risk of hemorrhage in 238 patients. Neurosurgery 63:8238312008

    • Search Google Scholar
    • Export Citation
  • 11

    Huang PPRush SCDonahue BNarayana ABecske TNelson PK: Long-term outcomes after staged-volume stereotactic radiosurgery for large arteriovenous malformations. Neurosurgery 71:6326442012

    • Search Google Scholar
    • Export Citation
  • 12

    Iosif CMendes GASaleme SPonomarjova SSilveira EPCaire F: Endovascular transvenous cure for ruptured brain arteriovenous malformations in complex cases with high Spetzler-Martin grades. J Neurosurg 122:122912382015

    • Search Google Scholar
    • Export Citation
  • 13

    Kano HKondziolka DFlickinger JCPark KJParry PVYang HC: Stereotactic radiosurgery for arteriovenous malformations, Part 6: multistaged volumetric management of large arteriovenous malformations. J Neurosurg 116:54652012

    • Search Google Scholar
    • Export Citation
  • 14

    Kano HKondziolka DFlickinger JCYang HCFlannery TJAwan NR: Stereotactic radiosurgery for arteriovenous malformations, Part 3: outcome predictors and risks after repeat radiosurgery. J Neurosurg 116:21322012

    • Search Google Scholar
    • Export Citation
  • 15

    Laakso ADashti RJuvela SIsarakul PNiemelä MHernesniemi J: Risk of hemorrhage in patients with untreated Spetzler-Martin grade IV and V arteriovenous malformations: a long-term follow-up study in 63 patients. Neurosurgery 68:3723782011

    • Search Google Scholar
    • Export Citation
  • 16

    Lawton MT: Seven AVMs: Tenets and Techniques for Resection. New YorkThieme2014. 313317

  • 17

    Ledezma CJHoh BLCarter BSPryor JCPutman CMOgilvy CS: Complications of cerebral arteriovenous malformation embolization: multivariate analysis of predictive factors. Neurosurgery 58:6026112006

    • Search Google Scholar
    • Export Citation
  • 18

    Mohr JPParides MKStapf CMoquete EMoy CSOverbey JR: Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 383:6146212014

    • Search Google Scholar
    • Export Citation
  • 19

    Moosa SChen CJDing DLee CCChivukula SStarke RM: Volume-staged versus dose-staged radiosurgery outcomes for large intracranial arteriovenous malformations. Neurosurg Focus 37:3E182014

    • Search Google Scholar
    • Export Citation
  • 20

    Paúl LCasasco AKusak MEMartinez NRey GMartinez R: Results for a series of 697 arteriovenous malformations treated by Gamma Knife: influence of angiographic features on the obliteration rate.. Neurosurgery 75:568563583:2014

    • Search Google Scholar
    • Export Citation
  • 21

    Pollock BEFlickinger JC: A proposed radiosurgery-based grading system for arteriovenous malformations. J Neurosurg 96:79852002

  • 22

    Pollock BEFlickinger JCLunsford LDBissonette DJKondziolka D: Factors that predict the bleeding risk of cerebral arteriovenous malformations. Stroke 27:161996

    • Search Google Scholar
    • Export Citation
  • 23

    Pollock BEKline RWStafford SLFoote RLSchomberg PJ: The rationale and technique of staged-volume arteriovenous malformation radiosurgery. Int J Radiat Oncol Biol Phys 48:8178242000

    • Search Google Scholar
    • Export Citation
  • 24

    Schäuble BCascino GDPollock BEGorman DAWeigand SCohen-Gadol AA: Seizure outcomes after stereotactic radiosurgery for cerebral arteriovenous malformations. Neurology 63:6836872004

    • Search Google Scholar
    • Export Citation
  • 25

    Schuster LSchenk EGiesel FHauser TGerigk LZabel-Du-Bois A: Changes in AVM angio-architecture and hemodynamics after stereotactic radiosurgery assessed by dynamic MRA and phase contrast flow assessments: a prospective follow-up study. Eur Radiol 21:126712762011

    • Search Google Scholar
    • Export Citation
  • 26

    Seymour ZASneed PKGupta NLawton MTMolinaro AMYoung W: Volume-staged radiosurgery for large arteriovenous malformations: an evolving paradigm. J Neurosurg 124:1631742016

    • Search Google Scholar
    • Export Citation
  • 27

    Sirin SKondziolka DNiranjan AFlickinger JCMaitz AHLunsford LD: Prospective staged volume radiosurgery for large arteriovenous malformations: indications and outcomes in otherwise untreatable patients. Neurosurgery 62:Suppl 27447542008

    • Search Google Scholar
    • Export Citation
  • 28

    Spetzler RFMartin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:4764831986

  • 29

    Stefani MAPorter PJterBrugge KGMontanera WWillinsky RAWallace MC: Large and deep brain arteriovenous malformations are associated with risk of future hemorrhage. Stroke 33:122012242002

    • Search Google Scholar
    • Export Citation
  • 30

    Taeshineetanakul PKrings TGeibprasert SMenezes RAgid RterBrugge KG: Angioarchitecture determines obliteration rate after radiosurgery in brain arteriovenous malformations. Neurosurgery 71:107110792012

    • Search Google Scholar
    • Export Citation
  • 31

    Valavanis AYaşargil MG: The endovascular treatment of brain arteriovenous malformations. Adv Tech Stand Neurosurg 24:1312141998

  • 32

    van Beijnum Jvan der Worp HBBuis DRAl-Shahi Salman RKappelle LJRinkel GJ: Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA 306:201120192011

    • Search Google Scholar
    • Export Citation
  • 33

    Walczak T: Surgical Treatment of the Epilepsies ed 2New YorkRaven Press1994

  • 34

    Xiao FGorgulho AALin CSChen CHAgazaryan NViñuela F: Treatment of giant cerebral arteriovenous mal formation: hypofractionated stereotactic radiation as the first stage. Neurosurgery 67:125312592010

    • Search Google Scholar
    • Export Citation
  • 35

    Zipfel GJBradshaw PBova FJFriedman WA: Do the morphological characteristics of arteriovenous malformations affect the results of radiosurgery?. J Neurosurg 101:3934012004

    • Search Google Scholar
    • Export Citation
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