Effect of treatment period on outcomes after stereotactic radiosurgery for brain arteriovenous malformations: an international multicenter study

View More View Less
  • 1 Department of Neurosurgery, University of Virginia, Charlottesville, Virginia;
  • 2 Department of Neurosurgery, University of Pittsburgh, Pennsylvania;
  • 3 Department of Neurological Surgery, University of Miami, Florida;
  • 4 Gamma Knife Center, University of Pennsylvania, Philadelphia, Pennsylvania;
  • 5 Department of Neurosurgery, University of Sherbrooke, Quebec, Canada;
  • 6 Gamma Knife Center, New York University, New York, New York;
  • 7 Department of Neurosurgery, University of Puerto Rico, San Juan, Puerto Rico;
  • 8 Gamma Knife Center, Beaumont Health System, Royal Oak, Michigan; and
  • 9 Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, Ohio
Full access

OBJECTIVE

The role of and technique for stereotactic radiosurgery (SRS) in the management of arteriovenous malformations (AVMs) have evolved over the past four decades. The aim of this multicenter, retrospective cohort study was to compare the SRS outcomes of AVMs treated during different time periods.

METHODS

The authors selected patients with AVMs who underwent single-session SRS at 8 different centers from 1988 to 2014 with follow-up ≥ 6 months. The SRS eras were categorized as early (1988–2000) or modern (2001–2014). Statistical analyses were performed to compare the baseline characteristics and outcomes of the early versus modern SRS eras. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RICs).

RESULTS

The study cohort comprised 2248 patients with AVMs, including 1584 in the early and 664 in the modern SRS eras. AVMs in the early SRS era were significantly smaller (p < 0.001 for maximum diameter and volume), and they were treated with a significantly higher radiosurgical margin dose (p < 0.001). The obliteration rate was significantly higher in the early SRS era (65% vs 51%, p < 0.001), and earlier SRS treatment period was an independent predictor of obliteration in the multivariate analysis (p < 0.001). The rates of post-SRS hemorrhage and radiological, symptomatic, and permanent RICs were not significantly different between the two groups. Favorable outcome was achieved in a significantly higher proportion of patients in the early SRS era (61% vs 45%, p < 0.001), but the earlier SRS era was not statistically significant in the multivariate analysis (p = 0.470) with favorable outcome.

CONCLUSIONS

Despite considerable advances in SRS technology, refinement of AVM selection, and contemporary multimodality AVM treatment, the study failed to observe substantial improvements in SRS favorable outcomes or obliteration for patients with AVMs over time. Differences in baseline AVM characteristics and SRS treatment parameters may partially account for the significantly lower obliteration rates in the modern SRS era. However, improvements in patient selection and dose planning are necessary to optimize the utility of SRS in the contemporary management of AVMs.

ABBREVIATIONS AVM = arteriovenous malformation; EBRT = external beam radiation therapy; GKRS = Gamma Knife radiosurgery; IGKRF = International Gamma Knife Research Foundation; RIC = radiation-induced change; SM = Spetzler-Martin; SRS = stereotactic radiosurgery; VRAS = Virginia Radiosurgery AVM Scale.

OBJECTIVE

The role of and technique for stereotactic radiosurgery (SRS) in the management of arteriovenous malformations (AVMs) have evolved over the past four decades. The aim of this multicenter, retrospective cohort study was to compare the SRS outcomes of AVMs treated during different time periods.

METHODS

The authors selected patients with AVMs who underwent single-session SRS at 8 different centers from 1988 to 2014 with follow-up ≥ 6 months. The SRS eras were categorized as early (1988–2000) or modern (2001–2014). Statistical analyses were performed to compare the baseline characteristics and outcomes of the early versus modern SRS eras. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RICs).

RESULTS

The study cohort comprised 2248 patients with AVMs, including 1584 in the early and 664 in the modern SRS eras. AVMs in the early SRS era were significantly smaller (p < 0.001 for maximum diameter and volume), and they were treated with a significantly higher radiosurgical margin dose (p < 0.001). The obliteration rate was significantly higher in the early SRS era (65% vs 51%, p < 0.001), and earlier SRS treatment period was an independent predictor of obliteration in the multivariate analysis (p < 0.001). The rates of post-SRS hemorrhage and radiological, symptomatic, and permanent RICs were not significantly different between the two groups. Favorable outcome was achieved in a significantly higher proportion of patients in the early SRS era (61% vs 45%, p < 0.001), but the earlier SRS era was not statistically significant in the multivariate analysis (p = 0.470) with favorable outcome.

CONCLUSIONS

Despite considerable advances in SRS technology, refinement of AVM selection, and contemporary multimodality AVM treatment, the study failed to observe substantial improvements in SRS favorable outcomes or obliteration for patients with AVMs over time. Differences in baseline AVM characteristics and SRS treatment parameters may partially account for the significantly lower obliteration rates in the modern SRS era. However, improvements in patient selection and dose planning are necessary to optimize the utility of SRS in the contemporary management of AVMs.

ABBREVIATIONS AVM = arteriovenous malformation; EBRT = external beam radiation therapy; GKRS = Gamma Knife radiosurgery; IGKRF = International Gamma Knife Research Foundation; RIC = radiation-induced change; SM = Spetzler-Martin; SRS = stereotactic radiosurgery; VRAS = Virginia Radiosurgery AVM Scale.

Stereotactic radiosurgery (SRS) is the mainstay of treatment for patients with brain arteriovenous malformations (AVMs), particularly for deep or eloquent lesions that carry high operative risks.4,5,11,20,40,41 Since Steiner et al. reported successful radiosurgical obliteration of an AVM in 1972,45 SRS techniques and technologies have evolved substantially.25,29 Advances in the radiological evaluation of AVMs, using both invasive and noninvasive imaging modalities, and in dose planning software have facilitated further refinements in SRS treatment. Multiisocentric SRS treatment plans with greater conformality have allowed greater shielding of adjacent brain parenchyma. SRS has also become an important part of multimodality AVM treatment along with embolization and resection, thereby expanding the numbers and types of AVMs treated at least in part with SRS.

In the last four decades, SRS has been shown to have an acceptable risk-to-benefit profile for a wide range of AVMs, and long-term data pertaining to obliteration, post-SRS hemorrhage, seizure outcomes, and early and late SRS-related complications have accrued.3,7–10,12–15,17–20,38 However, despite the advancement and evolution of SRS capabilities over time, it is unclear if the outcomes for patients with AVMs have improved accordingly.37 It is often noted that Gamma Knife radiosurgery (GKRS) began in the 1960s. However, routine use of GKRS in the US began in the mid- to late 1980s. Thus, the year 2000 marks a midpoint between the first approximately 15 years of routine GKRS use (the first dedicated clinical Gamma Knife unit was installed in 1987 at University of Pittsburgh Medical Center) and the approximately 15 years that followed. Therefore, the aim of this multicenter, retrospective cohort study is to compare the radiological and clinical outcomes of the early SRS era (1988–2000) with those of the modern SRS era (2001–2014) for the treatment of AVMs.

Methods

Patient Selection

We performed a retrospective assessment of data from patients with AVMs treated with SRS at 8 centers participating in the International Gamma Knife Research Foundation (IGKRF). Each contributing center received IRB approval for this study. The following inclusion criteria were used to identify and select the study cohort: 1) AVM patients with a minimum follow-up of 6 months after SRS; 2) treatment with single-session SRS; and 3) adequate baseline and outcomes data. All SRS procedures were performed using a common device, the Gamma Knife (Elekta AB).

Data from each institution was de-identified, evaluated for accuracy and completeness, and pooled by a central study controller for the IGKRF. The combined data were transferred to the senior author (J.P.S.) for analysis. Inconsistencies in the data were addressed by the contributing institution.

Baseline Data and Variables

The baseline data comprised patient, AVM, and SRS factors. The patient variables were age, sex, initial clinical presentation, and time interval from presentation to SRS. The AVM variables were prior interventions, prior hemorrhage, size (maximum diameter and volume), venous drainage pattern (exclusively superficial or deep component), location (eloquent or noneloquent), and presence of associated arterial aneurysms. The eloquent locations were previously defined by Spetzler and Martin as follows: “primary somatosensory, primary motor, language and visual cortices, internal capsule, hypothalamus and thalamus, brainstem, cerebellar peduncles, and deep cerebellar nuclei.”39 The Spetzler-Martin (SM) grade and Virginia Radiosurgery AVM Scale (VRAS) score were determined for each patient with an AVM.39,43

The SRS variables were year of treatment (dichotomized into early or late SRS era), margin dose, maximum dose, isodose line, and number of isocenters. Patients were divided into two groups: the early SRS era was composed of patients who were treated from 1988 to 2000, and the modern SRS era was composed of patients who were treated from 2001 to 2014.

GKRS Technique

The GKRS technique used at each contributing center has been previously described.44 In brief, a Leksell model G stereotactic frame (Elekta AB) was applied to the patient’s cranium under anesthesia. The angioarchitecture of the AVM nidus was assessed with thin-slice MRI (typical slice width approximately 1 mm) and cerebral angiography. Thin-slice CT was obtained in patients who were unable to undergo MRI or prior to availability of MRI. In the early era prior to CT, cases were planned using biplanar cerebral angiography alone. Dose planning including target delineation, defining of critical structures potentially at risk, and dose selection was performed by a multidisciplinary team consisting of a radiation oncologist, medical physicist, and neurosurgeon.

Follow-Up

Clinical and radiological follow-up were obtained simultaneously, when possible, typically at 6-month intervals for the first 2 years after SRS, and then annually thereafter. Clinical follow-up consisted of a review of hospital and clinic archives, either from the treating center or from a referring institution or local primary care physician. Each patient’s neurological status at the last clinical follow-up was compared with his or her baseline neurological status prior to SRS.

Radiological follow-up consisted of MRI or CT (whenever MRI was contraindicated), and angiography. We recommended angiography to confirm AVM obliteration determined by MRI, or to evaluate and better define a residual AVM nidus for additional treatment. Additional neuroimaging was performed in patients who developed new or deteriorating neurological symptoms following SRS.

On MRI, obliteration was defined as an absence of flow voids, or on angiography, as a lack of abnormal arteriovenous shunting. On MRI, radiation-induced changes (RICs) were defined as T2-weighted hyperintensities adjacent to the AVM nidus. Radiologically evident RICs accompanied by neurological symptoms were categorized as symptomatic RICs, and symptomatic RICs without neurological recovery were categorized as permanent RICs. Post-SRS latency hemorrhage was defined as any radiological evidence of AVM-related hemorrhage following SRS. Favorable outcome was defined as AVM obliteration without post-SRS hemorrhage or permanent RICs.

Statistical Analysis

Data are presented as mean and SD for continuous variables, and as frequency and percentage for categorical variables. Normality was assessed graphically and statistically. Categorical variables were compared using Pearson’s chi-square and Fisher’s exact tests, as appropriate. Continuous variables were compared using the unpaired Student t-test, with and without equal variance (Levene’s test), and the Wilcoxon rank-sum test, as appropriate. The patient, AVM, and SRS variables listed above were entered into univariate logistic regression analyses to identify factors associated with radiological RICs and favorable outcome. Factors with p values < 0.15 in the univariate analysis were further studied with a multivariate logistic regression analysis to determine independent predictors for each particular outcome. Clinically significant variables and interaction expansion covariates were further evaluated each multivariate analysis.

Results

Baseline Characteristics of the Early Versus Modern SRS Eras

The overall study cohort comprised 2248 patients, including 1584 treated during the early SRS era spanning 1988–2000 (70.4%) and 664 treated during the modern SRS era spanning 2001–2014 (29.6%). The contributions from each of the 8 centers participating in the study were as follows: 1012 patients from the University of Virginia, 798 from the University of Pittsburgh, 226 from Cleveland Clinic, 89 from New York University, 52 from the University of Sherbrooke, 33 from the University of Puerto Rico, 24 from the University of Pennsylvania, and 14 from Beaumont Health System.

Table 1 compares the patient and AVM characteristics of the early and modern SRS eras. Patients in the early SRS era were younger (mean age 34.6 vs 39.5 years, p < 0.001), with a longer duration between presentation and SRS (mean 32.7 vs 15.6 years, p < 0.001). Patients in the early SRS era were less likely to present with hemorrhage (54.2% vs 61.6%, p = 0.001) or be asymptomatic (1.4% vs 9.9%, p < 0.001), but were more likely to present with seizure (19.8% vs 14.3%, p = 0.002), headache (16.5% vs 10.1%, p < 0.001), and focal neurological deficit (8.0% vs 3.8%, p < 0.001).

TABLE 1.

Comparison of patient and AVM characteristics of the early (1988–2000) versus modern (2001–2014) SRS eras

VariableEarly SRS Era (n = 1584)Modern SRS Era (n = 664)p Value
Female sex (%)765 (48.3)348 (52.4)0.075
Mean age ± SD (yrs)34.6 ± 15.839.5 ± 17.5<0.001
Mean duration btwn presentation & SRS ± SD (mos)32.7 ± 95.415.6 ± 46.2<0.001
Clinical presentation (%)
 Hemorrhage859 (54.2)409 (61.6)0.001
 Seizure314 (19.8)95 (14.3)0.002
 Headache262 (16.5)67 (10.1)<0.001
 Focal neurological deficit126 (8.0)25 (3.8)<0.001
 Asymptomatic22 (1.4)66 (9.9)<0.001
Prior AVM embolization (%)352 (22.2)127 (19.1)0.102
Prior AVM resection (%)76 (4.8)28 (4.2)0.550
Prior EBRT (%)167 (10.5)19 (2.9)<0.001
Prior AVM hemorrhage (%)853 (53.9)410 (61.7)0.001
Mean max AVM diameter ± SD (cm)2.3 ± 0.92.6 ± 1.7<0.001
Mean AVM volume ± SD (cm3)3.9 ± 3.65.6 ± 7.2<0.001
Deep venous drainage (%)913 (57.6)358 (53.9)0.104
Eloquent AVM location (%)1129 (71.3)428 (64.5)0.001
Associated arterial aneurysms (%)151 (9.5)118 (17.8)<0.001
SM grade (%)*<0.001
 I152 (9.6)90 (13.6)
 II595 (37.6)241 (36.3)
 III694 (43.8)239 (36.0)
 IV139 (8.8)76 (11.4)
 V3 (0.2)18 (2.7)
VRAS score (%)0.108
 089 (5.6)41 (6.2)
 1384 (24.2)158 (23.9)
 2409 (25.8)164 (24.8)
 3433 (27.3)157 (23.8)
 4269 (17.0)141 (21.3)

Data given as number of patients (%) unless otherwise indicated. Boldface type indicates statistical significance.

Data available for 2247 of 2248 patients, including 1583 of 1584 patients in the early SRS era and all 664 patients in the modern SRS era groups.

Data available for 2245 of 2248 patients, including all 1584 patients in the early SRS era and 661 of 664 patients in the modern SRS era groups.

AVMs in the early SRS era had more commonly undergone prior fractionated external beam radiation therapy (EBRT; 10.5% vs 2.9%, p < 0.001). The frequency of prior AVM hemorrhage was lower in the early SRS era (53.9% vs 61.7%, p = 0.001). AVMs in the early SRS era were smaller, by both maximum diameter (mean 2.3 vs 2.6 cm, p < 0.001) and volume (mean 3.9 vs 5.6 cm3, p < 0.001), more commonly located in eloquent areas (71.3% vs 64.5%, p = 0.001), and less likely to have associated arterial aneurysms (9.5% vs 17.8%, p < 0.001). Patients in the early SRS era had a lower SM grade (p < 0.001).

Table 2 compares the SRS parameters of the early and modern SRS eras. Treatment plans in the early SRS era used a higher margin dose (mean 20.7 vs 19.7 Gy, p < 0.001), lower maximum dose (38.2 vs 39.2 Gy, p = 0.004), higher isodose line (55.2% vs 50.6%, p < 0.001), and fewer isocenters (2.7 vs 7.0, p < 0.001).

TABLE 2.

Comparison of SRS parameters of the early (1988–2000) versus modern (2001–2014) SRS eras

SRS ParameterEarly SRS Era (n = 1584)Modern SRS Era (n = 664)p Value
Mean margin dose ± SD (Gy)20.7 ± 3.519.7 ± 4.2<0.001
Mean max dose ± SD (Gy)38.2 ± 7.239.2 ± 8.30.004
Mean isodose line ± SD (%)55.2 ± 10.950.6 ± 2 .9<0.001
Mean no. isocenters ± SD2.7 ± 1.97.0 ± 5.1<0.001

Boldface type indicates statistical significance.

Outcomes of the Early Versus Modern SRS Eras

Table 3 compares the outcomes after SRS for the early and modern SRS eras. The crude obliteration rate was significantly higher in the early SRS era (64.9% vs 51.4%, p < 0.001).

TABLE 3.

Comparison of outcomes after SRS for the early (1988–2000) versus modern (2001–2014) SRS eras

OutcomeEarly SRS Era (n = 1584)Modern SRS Era (n = 664)p Value
Obliteration (%)1028 (64.9)341 (51.4)<0.001
Post-SRS hemorrhage (%)134 (8.5)49 (7.4)0.393
Radiological RICs (%)475 (30.0)177 (26.7)0.112
Symptomatic RICs (%)141 (8.9)73 (11.0)0.123
Permanent RICs (%)36 (2.3)23 (3.5)0.107
Favorable outcome (%)960 (60.6)301 (45.3)<0.001
Mean follow-up duration ± SD (mos)98.8 ± 65.145.0 ± 29.6<0.001

Favorable outcome = AVM obliteration, no post-SRS hemorrhage, and no permanent RICs.

Data given as number of patients (%) unless otherwise indicated. Boldface type indicates statistical significance.

Table 4 details the univariate and multivariate Cox proportional regression analyses for predictors of obliteration. In the multivariate analysis, early SRS era (p < 0.001), lack of prior AVM EBRT (p = 0.013), lack of prior AVM embolization (p < 0.001), smaller AVM maximum diameter (p < 0.001), smaller AVM volume (p = 0.008), higher margin dose (p < 0.001), and higher maximum dose (p = 0.012) were found to be independent predictors of obliteration. The annual post-SRS hemorrhage rate prior to obliteration was not statistically different between the two groups (p = 0.459).

TABLE 4.

Univariate and multivariate Cox proportional hazards regression analyses for predictors of AVM obliteration after SRS

Univariate AnalysisMultivariate Analysis
VariableHR95% CIp ValueHR95% CIp Value
Early SRS era1.911.67–2.17<0.0011.791.56–2.05<0.001
Older age1.011.00–1.010.001NS
No prior AVM hemorrhage1.100.99–1.220.083NS
No prior AVM EBRT1.180.99–1.410.0641.261.05–1.520.013
No prior AVM embolization1.891.63–2.19<0.0011.551.33–1.80<0.001
Smaller AVM max diameter1.491.40–1.58<0.0011.311.22–1.41<0.001
Smaller AVM volume1.111.09–1.13<0.0011.031.01–1.060.008
Lower SM grade*1.301.22–1.39<0.001
Lower VRAS score*1.301.24–1.36<0.001
Higher margin dose1.091.07–1.10<0.0011.051.03–1.07<0.001
Higher max dose1.041.03–1.05<0.0011.011.00–1.020.012
No radiological RICs1.100.98–1.230.117NS

NS = not significant in the multivariate analysis (p ≥ 0.05).

Only factors with p values < 0.15 in the univariate analysis were listed in the multivariate analysis. Boldface type indicates statistical significance.

Grading scales not included in the multivariate analysis.

If we further limited the cohorts to a minimum follow-up of 3 years, this would lead to 1261 patients in the early era and 319 patients in the modern era. Analyzing these patients demonstrated no statistical differences in obliteration (64.23% for early and 63.95% for the modern era, p = 0.924) and favorable outcome (40.84% for early and 38.78% for the modern era, p = 0.507).

Radiation-Induced Changes

The early and modern SRS eras did not have significantly different rates of radiological (p = 0.112), symptomatic (p = 0.123) or permanent (p = 0.107) RICs (Table 3). Table 5 details the univariate and multivariate logistic regression analyses for predictors of radiological RICs. In the multivariate analysis, only larger AVM volume (p = 0.027) and lower margin dose (p < 0.001) were found to be independent predictors of radiological RICs. SRS treatment era was not significantly associated with radiological RICs in the univariate analysis (p = 0.223).

TABLE 5.

Univariate and multivariate logistic regression analyses for predictors of radiological RICs

Univariate AnalysisMultivariate Analysis
VariableOR95% CIp ValueOR95% CIp Value
Older age1.000.99–1.010.150NS
Prior AVM hemorrhage1.211.01–1.460.040NS
No prior AVM EBRT1.611.12–2.330.010NS
Prior AVM embolization1.240.99–1.540.056NS
Larger AVM max diameter1.231.12–1.34<0.001NS
Larger AVM volume1.021.01–1.040.0091.071.01–1.130.027
Lower margin dose1.051.02–1.07<0.0011.081.04–1.12<0.001
Lower max dose1.011.00–1.020.074NS
Higher VRAS score*1.241.15–1.34<0.001
AVM obliteration1.291.06–1.570.010NS

Only factors with p values < 0.15 in the univariate analysis were listed in the multivariate analysis. Boldface type indicates statistical significance.

Grading scales were not included in the multivariate analysis.

Favorable outcome as defined by the combined result of AVM obliteration, no post-SRS hemorrhage, and no permanent RICs was achieved in a significantly higher proportion of patients in the early SRS era (60.6% early vs 45.3% late eras, p < 0.001; Table 3). Table 6 further details the univariate and multivariate logistic regression analyses for predictors of favorable outcome after SRS. In the multivariate analysis, lack of prior AVM hemorrhage (p < 0.001), no prior AVM embolization (p < 0.001), smaller AVM volume (p < 0.001), absence of associated arterial aneurysms (p < 0.001), and higher margin dose (p < 0.001) were found to be independent predictors of favorable outcome. Although the early SRS era was significantly associated with favorable outcome in the univariate analysis (OR 1.49, 95% CI 1.23–1.80; p < 0.001), it was not found to be predictive in the multivariate analysis (p = 0.470).

TABLE 6.

Univariate and multivariate logistic regression analyses for predictors of favorable outcome after SRS

Univariate AnalysisMultivariate Analysis
VariableOR95% CIp ValueOR95% CIp Value
Early SRS era1.491.23–1.80<0.001NS
Older age1.001.00–1.010.141NS
No prior AVM hemorrhage1.180.99–1.400.0591.391.20–1.54<0.001
No prior AVM EBRT1.581.14–2.170.006NS
No prior AVM embolization2.281.85–2.82<0.0011.941.46–2.58<0.001
Smaller AVM max diameter1.981.80–2.19<0.001NS
Smaller AVM volume1.191.16–1.23<0.0011.101.05–1.14<0.001
No associated aneurysms1.631.25–2.12<0.0011.831.27–2.65<0.001
Noneloquent AVM location1.391.15–1.670.001NS
Exclusively superficial venous drainage1.191.00–1.420.047NS
Lower SM grade*1.701.53–1.90<0.001
Lower VRAS score*1.611.49–1.74<0.001
Higher margin dose1.231.20–1.27<0.0011.131.08–1.19<0.001
Higher max dose1.071.06–1.08<0.001NS

Only factors with p values < 0.15 in the univariate analysis were listed in the multivariate analysis. Boldface type indicates statistical significance.

Grading scales were not included in the multivariate analysis.

Discussion

SRS has been widely adopted as a treatment modality for the management of AVMs, and, for many patients with AVMs, it is an effective alternative and at times preferred option to resection or curative embolization.12,16,19,24,34,35,42,48 Some early SRS treatments of AVMs were planned based only on angiography, prior to the widespread availability of CT and MRI. Later, CT and then MRI were routinely integrated into radiosurgical dose planning. This added additional 3D data that better delineated AVM morphology in the axial plane. SRS of AVMs that are supplied by both the anterior and posterior circulation may have been difficult without the implementation of CT and/or MRI to define the 3D spatial anatomy of the entire nidus and adjacent critical structures. Advances in noninvasive imaging modalities, such as high-resolution MR and CT angiography, have allowed more detailed characterization of the AVM nidus to be incorporated into SRS planning.28

One of the early analyses of AVM SRS arose from a cohort of 247 patients treated by Steiner prior to 1984 using the second version of the Gamma Knife with 179 cobalt-60 (60Co) sources (compared with 201 60Co sources in models U, B, and C, and 192 60Co sources in the Perfexion) with collimator sizes of 4, 8, and 14 mm, similar to collimator sizes of 4, 8, 14, 16, and 18 mm in later models.44 Obliteration was reported in 81% of cases, and the annual latency period hemorrhage rate was 3.7%. In this early report, the vast majority of AVMs had ruptured prior to SRS (94%). The majority of patients experienced at least partial recovery of their preoperative neurological symptoms. However, despite the detailed clinical outcomes reported in this study, there was a paucity of data provided regarding AVM size, nidal angioarchitecture, or SRS parameters.

Flickinger et al. described the relationships among SRS margin dose, AVM volume, in-field obliteration, and overall nidal obliteration.23 Margin dose was predictive of in-field obliteration but not nidal obliteration. In contrast, volume was predictive of nidal obliteration, but not in-field obliteration. Furthermore, 35 (63.6%) of 55 patients with residual AVMs had incomplete targeting of the original nidus. This emphasizes the importance of proper definition of the AVM’s anatomy, as well was careful treatment planning that includes the entirety of the lesion.46 A subsequent study showed that the 12 Gy volume was significantly associated with RICs, which indicates the contribution of conformal dose planning and steep gradient indices to successful AVM SRS outcomes.22

Changes in SRS practices over time have improved outcomes for some lesions, such as acoustic neuromas.21 Specifically, the use of multiisocentric treatment plans with greater conformality and lower margin doses have resulted in improved trigeminal and facial nerve outcomes, as well as higher rates of hearing preservation,47 but improvements in SRS outcomes for AVMs have not proven similarly consistent. Nagy et al.30 analyzed a cohort of 492 large AVMs (volume > 10 cm3) treated with single-session SRS, and categorized the cases into three treatment periods based on the time of SRS. During the first, less conformal angiography–based period (1986–1993), treatment plans consisted of a median margin dose of 23 Gy and 2 isocenters covering 45%–70% of the AVM (median volume 15.7 cm3). During the second, more conformal angiographic–based period (1994–2000), treatment plans consisted of a median margin dose of 21 Gy and 5 isocenters covering 64%–95% of the AVM (median volume 14.6 cm3). During the third MRI period (2001–2007), treatment plans consisted of a median margin dose of 21 Gy and 7 isocenters covering 62%–94% of the AVM (median volume 14.3 cm3). The use of pre-SRS embolization increased during the study periods. When these partially embolized AVMs were excluded from the analysis, the obliteration rate increased from the first (28%) to the third (63%) treatment period, without a significant change in the rates of RICs.

A single-center cohort study investigated 381 AVMs treated with SRS from 1990 to 2009, and compared patients treated from January 1990 to March 1997 (group 1, n = 160) to those treated from April 1997 to December 2009 (group 2, n = 221).37 Group 1 had a significantly higher obliteration rate (p < 0.001) but also had a significantly higher rate of radiation-induced complications (p = 0.02). The rate of post-SRS hemorrhage was not significantly different between the two groups. The authors attributed their findings to improvements in newer generation GKRS platforms, volume-staged SRS, a greater number of isocenters per dose plan, and better conformality index.

In the present study, we analyzed the largest multicenter cohort of 2248 AVMs treated with single-session SRS, and compared the results of the early (1988–2000) and modern (2001–2014) SRS eras. The crude rates of obliteration (65% vs 51%, p < 0.001) and favorable outcome (61% vs 45%, p < 0.001) were both significantly higher in the early SRS era, although the rates of post-SRS hemorrhage and RIC were not significantly different between the two groups. In the multivariate analysis, early SRS era was found to be an independent predictor of obliteration (p < 0.001). However, early SRS era was not significant in the multivariate analysis for favorable outcome. These findings suggest that the inferior or almost similar outcomes for AVMs treated during the modern SRS era may be partially attributed to differences in the baseline characteristics and follow-up durations of the two groups. Specifically, AVMs in the early SRS era were smaller, by diameter (p < 0.001) and volume (p < 0.001), and the margin dose used for their treatment was significantly higher (p < 0.001). However, both groups exhibited a median nidus volume well under that which is typically appropriate for single-session SRS (approximately 12 cm3), and none of the patients included in this study underwent volume- or dose-staged SRS (typically used for larger-volume AVMs). Because both nidus volume and radiosurgical dose are intimately related to obliteration, the differences in variables could have affected the observed outcomes after SRS.23 The significantly longer follow-up duration of the early SRS cohort (mean 99 vs 45 months, p < 0.001) may also have influenced the discrepancy between the obliteration rates of the two treatment periods.

The latency period of GKRS is approximately 3 years for most patients with AVMs. If we further limited the cohorts to a minimum follow-up of 3 years, this resulted in no statistical differences in obliteration (64.23% for the early and 63.95% for the modern era, p = 0.924) and favorable outcome (40.84% for the early and 38.78% for the modern era, p = 0.507). However, in excluding patients with less than 3 years of follow up, such an analysis introduces a selection bias by not analyzing time from delivery of SRS as a continuous variable and eliminating patients with early complications or early obliteration prior to 3 years if such patients have follow-up durations less than a 3-year cutoff threshold. Yet, this does demonstrate the potential effect of bias with including patients with shorter follow-up durations in the analysis for a procedure with generally delayed favorable and, occasionally, unfavorable results and an underlying cerebrovascular pathology of AVM with a low annual rate of hemorrhage.

We posit a number of possible reasons for the lack of improvement in AVM SRS outcomes over time. First, as practitioners gain more familiarity with SRS techniques for AVMs and outcomes data accumulates, SRS indications for AVMs broadened. As a result, SRS is being used to treat a wider range of lesions, including more complex nidi and larger volumes. As evidence of this, we noted that AVMs in the modern SRS cohort were more likely to have associated aneurysms (p < 0.001), with a greater proportion of high SM grade lesions (p < 0.001) and higher SM grade (p < 0.001). Second, current dose plans may be too conformal, with the goal of decreasing RIC rates. Treatment plans in the modern SRS cohort used a significantly greater number of isocenters (mean 7.0 vs 2.7, p < 0.001) perhaps with the intent on improving conformality but possibly leading to undertreating the AVM nidus itself. As Pan et al.33 have suggested, obliteration of an AVM may be enhanced when the percentage volume of the AVM receives a minimum dose of 20–23 Gy. A focus on reducing the dose to the 12 Gy volume may reduce the risk of RICs but at the expense of AVM obliteration. Third, the margin doses presently used for AVMs may be too low. Taken together, the relatively higher number of isocenters suggestive of a more conformal plan and lower prescription dose to the nidus of radiosurgical plans in the modern SRS era may have resulted in insufficient irradiation of arteriovenous shunts at the borders of the nidus. Finally, although not applicable to our study, partial embolization prior to SRS may be performed with greater frequency in the contemporary management of AVMs.10,30 Pre-SRS embolization has been shown in prior studies to adversely affect obliteration rates, although the underlying mechanisms have yet to be thoroughly deciphered.1,2,26,32 However, in the current study, the rates of prior embolization in the early and modern era cohorts were not statistically different, but this does not take into account differences in embolization techniques and materials that have evolved in the last 2 decades.

Over the past 3 decades, there may also have been a change in the risk tolerance of neurosurgeons. The response of AVMs to radiosurgery is one of delayed gratification as obliteration is not typically achieved for 1–3 years after radiosurgery. While margin doses of 20–25 Gy were more commonly delivered in the early era of radiosurgery, lower doses of 16–18 Gy have been used (Fig. 1) more commonly in the modern era so as to lessen the risk of radiation injury. We also found a trend of treatment of larger AVMs (Fig. 2) with complex nidal architecture. Such changes could impact the overall outcomes seen as a function of SRS era. We believe that the findings in this analysis according to radiosurgical era are novel and suggest opportunities for improvement in patient selection (e.g., smaller nidus volumes) and radiosurgical technique (e.g., higher dose selection) that could lead to more favorable outcomes in the modern era of SRS.

Fig. 1.
Fig. 1.

Box-and-whiskers plot showing the linear decreasing trend of marginal dose to the year of SRS treatment. Figure is available in color online only.

Fig. 2.
Fig. 2.

Box-and-whiskers plot showing the linear increasing trend of AVM volume to the year of SRS treatment. Figure is available in color online only.

Study Limitations

Although our study’s multicenter design mitigates many inherent selection, treatment, and referral biases, it remains limited by its retrospective nature. For instance, more patients in the early cohort received pre-SRS radiation therapy. One could argue that prior radiation could have affected obliteration in favorable (more overall radiation was delivered to the nidus) or unfavorable (prior radiation therapy could have resulted in a lower dose selected at the time of radiosurgery) fashions. The difference could be a confounding variable for the various end points. We were unable to determine the proportion of patients in the early SRS period that had treatment plans based on angiography alone.

The study also fails to fully account for differences in angioarchitectural features of the AVMs from a radiosurgical endpoint. In fact, there is no complete agreement on what constitutes comparable features for AVM stratification from a radiosurgical standpoint. Many such systems have been proposed including the SM and VRAS system.41 We did evaluate another system that showed that the number of major feeding arteries and draining veins to the nidus32 related to a feature of angioarchitectural complexity and was an independent prognostic factor of obliteration. However, our current data does not have information sufficient to apply this angioarchitectural complexity score. Also, we believe that the changes in patient selection (ones with a larger AVM nidus) and treatment approach (e.g., lower doses) are important factors to maintain in the analysis as they are reflective of the changes in SRS management of AVMs in the era. We illustrate these changes in AVM volume and dose as a function of study period in the figures. These changes are also noted to serve as a driver of poorer overall obliteration. Calling attention to these changes as part of the study findings may help to alter treatment approaches moving forward. However, differences in angioarchitectural features between the two cohorts could have resulted in obliteration differences in the early versus late eras.

Additionally, we were unable to evaluate the conformalities and gradient indices of the dose plans, and their effect on SRS outcomes. Although we did not find a significant difference between the rates of pre-SRS embolization in the early versus modern SRS eras, we could not account for the evolution of AVM embolization techniques, endovascular devices, and embolic agents over time.6 Furthermore, the salvage treatments were not noted for those patients who had patent AVMs in this study.

Obliteration was determined on the basis of MRI and/or angiography. While MRI was less accessible for surveillance imaging and targeting of radiosurgical planning in the early era, the rates of obliteration between eras were not likely affected by access to neuroimaging as MRI and angiography have fairly similar concordance rates for confirming obliteration.27 Approximately 13% of patients in each era in this study were determined to have obliteration based solely on MRI, which may falsely elevate the obliteration rate. However, recent studies have shown that MRI is a reasonably accurate substitute to angiography for the assessment of AVM obliteration after SRS.27,31,36 Lack of MRI for radiosurgical planning in some of the early era patients with AVMs could have impacted obliteration, RIC, and favorable outcome end points. Finally, detailed clinical statuses were not available for some patients included in this study. Therefore, we were unable to compare the long-term functional outcomes of the early and modern SRS eras.

Conclusions

Our comparative analysis of AVMs treated during the early versus modern SRS eras failed to identify significant improvements in outcomes over time, with respect to obliteration, latency period hemorrhage, or SRS-related complications. Therefore, it is unclear if advances in SRS techniques and technology have noticeably improved outcomes for patients with AVMs. It is possible that differences in AVM characteristics, patient selection, and SRS treatment parameters may somewhat account for the significantly lower obliteration rate of the modern SRS era, such that we are currently using SRS to treat a wider range of nidi with greater angioarchitectural complexity. However, it is incumbent on contemporary SRS practitioners to identify potential areas for continued improvement so that AVM outcomes improve following SRS. Better balancing of the percentage volume of the AVM receiving a higher dose (e.g., 20–25 Gy) and the brain volume receiving 12 Gy may restore the greater overall success rates of the earlier era.

Disclosures

Dr. Grills reports having stock ownership and serving on the Board of Directors in a company called Greater Michigan Gamma Knife, and Dr. Grills reports receiving funding for non–study-related research from Elekta through her institution. Dr. Lunsford reports owning stock in Elekta and being a consultant for Insightec and DSMB.

Author Contributions

Conception and design: Sheehan, Patibandla, Ding. Acquisition of data: Kano, Starke, Lee, Mathieu, Whitesell, Pierce, Huang, Feliciano, Rodriguez-Mercado, Almodovar, Grills, Silva, Abbassy, Missios, Barnett. Analysis and interpretation of data: Sheehan, Patibandla, Ding, Starke. Drafting the article: Sheehan, Patibandla, Ding. Critically revising the article: Sheehan, Patibandla, Ding, Kondziolka, Lunsford. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Sheehan. Statistical analysis: Starke. Administrative/technical/material support: Sheehan.

References

  • 1

    Andrade-Souza YM, Ramani M, Scora D, Tsao MN, terBrugge K, Schwartz ML: Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery 60:443452, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Buell TJ, Ding D, Starke RM, Webster Crowley R, Liu KC: Embolization-induced angiogenesis in cerebral arteriovenous malformations. J Clin Neurosci 21:18661871, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Chen CJ, Chivukula S, Ding D, Starke RM, Lee CC, Yen CP, : Seizure outcomes following radiosurgery for cerebral arteriovenous malformations. Neurosurg Focus 37(3):E17, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Cohen-Inbar O, Ding D, Chen CJ, Sheehan JP: Stereotactic radiosurgery for deep intracranial arteriovenous malformations, part 1: Brainstem arteriovenous malformations. J Clin Neurosci 24:3036, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Cohen-Inbar O, Ding D, Sheehan JP: Stereotactic radiosurgery for deep intracranial arteriovenous malformations, part 2: Basal ganglia and thalamus arteriovenous malformations. J Clin Neurosci 24:3742, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Crowley RW, Ducruet AF, McDougall CG, Albuquerque FC: Endovascular advances for brain arteriovenous malformations. Neurosurgery 74 (Suppl 1):S74S82, 2014

    • Search Google Scholar
    • Export Citation
  • 7

    Ding D: Influence of angioarchitecture on management of pediatric intracranial arteriovenous malformations. J Neurointerv Surg 8:e11, 2016

  • 8

    Ding D: Predicting outcomes from radiosurgery for intracranial arteriovenous malformations: effect of embolization, prior hemorrhage, and nidus anatomy. Neurol Sci 36:10251026, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Ding D, Liu KC: Predictive capability of the Spetzler-Martin versus Supplementary Grading Scale for microsurgical outcomes of cerebellar arteriovenous malformations. J Cerebrovasc Endovasc Neurosurg 15:307310, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Ding D, Sheehan JP, Starke RM, Durst CR, Raper DM, Conger JR, : Embolization of cerebral arteriovenous malformations with silk suture particles prior to stereotactic radiosurgery. J Clin Neurosci 22:16431649, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Ding D, Starke RM, Kano H, Lee JY, Mathieu D, Pierce J, : Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations: an international multicenter study. J Neurosurg 126:859871, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Ding D, Starke RM, Kano H, Mathieu D, Huang P, Kondziolka D, : Radiosurgery for cerebral arteriovenous malformations in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)-eligible patients: a multicenter study. Stroke 47:342349, 2016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Ding D, Xu Z, Shih HH, Starke RM, Yen CP, Sheehan JP: Stereotactic radiosurgery for partially resected cerebral arteriovenous malformations. World Neurosurg 85:263272, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Ding D, Xu Z, Starke RM, Yen CP, Shih HH, Buell TJ, : Radiosurgery for cerebral arteriovenous malformations with associated arterial aneurysms. World Neurosurg 87:7790, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Ding D, Xu Z, Yen CP, Starke RM, Sheehan JP: Radiosurgery for cerebral arteriovenous malformations in elderly patients: effect of advanced age on outcomes after intervention. World Neurosurg 84:795804, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Ding D, Xu Z, Yen CP, Starke RM, Sheehan JP: Radiosurgery for unruptured cerebral arteriovenous malformations in pediatric patients. Acta Neurochir (Wien) 157:281291, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Ding D, Yen CP, Starke RM, Xu Z, Sheehan JP: Radiosurgery for ruptured intracranial arteriovenous malformations. J Neurosurg 121:470481, 2014

  • 18

    Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP: Radiosurgery for low-grade intracranial arteriovenous malformations. J Neurosurg 121:457467, 2014

  • 19

    Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP: Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg 118:958966, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP: Radiosurgery for primary motor and sensory cortex arteriovenous malformations: outcomes and the effect of eloquent location. Neurosurgery 73:816824, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Flickinger JC, Kondziolka D, Niranjan A, Lunsford LD: Results of acoustic neuroma radiosurgery: an analysis of 5 years’ experience using current methods. J Neurosurg 119 Suppl:16, 2013

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Flickinger JC, Kondziolka D, Pollock BE, Maitz AH, Lunsford LD: Complications from arteriovenous malformation radiosurgery: multivariate analysis and risk modeling. Int J Radiat Oncol Biol Phys 38:485490, 1997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Flickinger JC, Pollock BE, Kondziolka D, Lunsford LD: A dose-response analysis of arteriovenous malformation obliteration after radiosurgery. Int J Radiat Oncol Biol Phys 36:873879, 1996

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Hong CS, Peterson EC, Ding D, Sur S, Hasan D, Dumont AS, : Intervention for A randomized trial of unruptured brain arteriovenous malformations (ARUBA) – eligible patients: an evidence-based review. Clin Neurol Neurosurg 150:133138, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Ilyas A, Chen CJ, Ding D, Taylor DG, Moosa S, Lee CC, : Volume-staged versus dose-staged stereotactic radiosurgery outcomes for large brain arteriovenous malformations: a systematic review. J Neurosurg [epub ahead of print January 27, 2017. DOI: 10.3171/2016.9.JNS161571]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Kano H, Kondziolka D, Flickinger JC, Park KJ, Iyer A, Yang HC, : Stereotactic radiosurgery for arteriovenous malformations after embolization: a case-control study. J Neurosurg 117:265275, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Lee CC, Reardon MA, Ball BZ, Chen CJ, Yen CP, Xu Z, : The predictive value of magnetic resonance imaging in evaluating intracranial arteriovenous malformation obliteration after stereotactic radiosurgery. J Neurosurg 123:136144, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Mokin M, Dumont TM, Levy EI: Novel multimodality imaging techniques for diagnosis and evaluation of arteriovenous malformations. Neurol Clin 32:225236, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Moosa S, Chen CJ, Ding D, Lee CC, Chivukula S, Starke RM, : Volume-staged versus dose-staged radiosurgery outcomes for large intracranial arteriovenous malformations. Neurosurg Focus 37(3):E18, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Nagy G, Rowe JG, Radatz MW, Hodgson TJ, Coley SC, Kemeny AA: A historical analysis of single-stage gamma knife radiosurgical treatment for large arteriovenous malformations: evolution and outcomes. Acta Neurochir (Wien) 154:383394, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    OʼConnor TE, Friedman WA: Magnetic resonance imaging assessment of cerebral arteriovenous malformation obliteration after stereotactic radiosurgery. Neurosurgery 73:761766, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Oermann EK, Ding D, Yen CP, Starke RM, Bederson JB, Kondziolka D, : Effect of prior embolization on cerebral arteriovenous malformation radiosurgery outcomes: a case-control study. Neurosurgery 77:406417, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Pan DHC, Guo WY, Chung WY, Shiau CY, Chang YC, Wang LW: Gamma knife radiosurgery as a single treatment modality for large cerebral arteriovenous malformations. J Neurosurg 93 (3 Suppl 3):113119, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Patibandla MR, Ding D, Kano H, Xu Z, Lee JYK, Mathieu D, : Stereotactic radiosurgery for Spetzler-Martin Grade IV and V arteriovenous malformations: an international multicenter study. J Neurosurg [epub ahead of print September 8, 2017. DOI: 10.3171/2017.3.JNS162635]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Patibandla MR, Ding D, Xu Z, Sheehan JP: Stereotactic radiosurgery for pediatric high-grade brain arteriovenous malformations: our experience and review of literature. World Neurosurg 102:613622, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Pollock BE, Kondziolka D, Flickinger JC, Patel AK, Bissonette DJ, Lunsford LD: Magnetic resonance imaging: an accurate method to evaluate arteriovenous malformations after stereotactic radiosurgery. J Neurosurg 85:10441049, 1996

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Pollock BE, Link MJ, Stafford SL, Garces YI, Foote RL: Stereotactic radiosurgery for arteriovenous malformations: the effect of treatment period on patient outcomes. Neurosurgery 78:499509, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Przybylowski CJ, Ding D, Starke RM, Yen CP, Quigg M, Dodson B, : Seizure and anticonvulsant outcomes following stereotactic radiosurgery for intracranial arteriovenous malformations. J Neurosurg 122:12991305, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:476483, 1986

  • 40

    Starke RM, Ding D, Kano H, Mathieu D, Huang PP, Feliciano C, : International multicenter cohort study of pediatric brain arteriovenous malformations. Part 2: Outcomes after stereotactic radiosurgery. J Neurosurg Pediatr 19:136148, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Starke RM, Kano H, Ding D, Lee JY, Mathieu D, Whitesell J, : Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. J Neurosurg 126:3644, 2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    Starke RM, Sheehan JP, Ding D, Liu KC, Kondziolka D, Crowley RW, : Conservative management or intervention for unruptured brain arteriovenous malformations. World Neurosurg 82:e668e669, 2014

    • Search Google Scholar
    • Export Citation
  • 43

    Starke RM, Yen CP, Ding D, Sheehan JP: A practical grading scale for predicting outcome after radiosurgery for arteriovenous malformations: analysis of 1012 treated patients. J Neurosurg 119:981987, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Steiner L, Lindquist C, Adler JR, Torner JC, Alves W, Steiner M: Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg 77:18, 1992

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Steiner L, Leksell L, Greitz T, Forster DM, Backlund EO: Stereotaxic radiosurgery for cerebral arteriovenous malformations. Report of a case. Acta Chir Scand 138:459464, 1972

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Valle RD, Zenteno M, Jaramillo J, Lee A, De Anda S: Definition of the key target volume in radiosurgical management of arteriovenous malformations: a new dynamic concept based on angiographic circulation time. J Neurosurg 109 Suppl:4150, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Yang I, Sughrue ME, Han SJ, Aranda D, Pitts LH, Cheung SW, : A comprehensive analysis of hearing preservation after radiosurgery for vestibular schwannoma: clinical article. J Neurosurg 119 Suppl:851859, 2013

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Yen CP, Ding D, Cheng CH, Starke RM, Shaffrey M, Sheehan J: Gamma Knife surgery for incidental cerebral arteriovenous malformations. J Neurosurg 121:10151021, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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

Contributor Notes

Correspondence Jason Sheehan: University of Virginia, Charlottesville, VA. jps2f@virginia.edu.

INCLUDE WHEN CITING Published online February 2, 2018; DOI: 10.3171/2017.8.JNS171336.

Disclosures Dr. Grills reports having stock ownership and serving on the Board of Directors in a company called Greater Michigan Gamma Knife, and Dr. Grills reports receiving funding for non–study-related research from Elekta through her institution. Dr. Lunsford reports owning stock in Elekta and being a consultant for Insightec and DSMB.

  • View in gallery

    Box-and-whiskers plot showing the linear decreasing trend of marginal dose to the year of SRS treatment. Figure is available in color online only.

  • View in gallery

    Box-and-whiskers plot showing the linear increasing trend of AVM volume to the year of SRS treatment. Figure is available in color online only.

  • 1

    Andrade-Souza YM, Ramani M, Scora D, Tsao MN, terBrugge K, Schwartz ML: Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery 60:443452, 2007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Buell TJ, Ding D, Starke RM, Webster Crowley R, Liu KC: Embolization-induced angiogenesis in cerebral arteriovenous malformations. J Clin Neurosci 21:18661871, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Chen CJ, Chivukula S, Ding D, Starke RM, Lee CC, Yen CP, : Seizure outcomes following radiosurgery for cerebral arteriovenous malformations. Neurosurg Focus 37(3):E17, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Cohen-Inbar O, Ding D, Chen CJ, Sheehan JP: Stereotactic radiosurgery for deep intracranial arteriovenous malformations, part 1: Brainstem arteriovenous malformations. J Clin Neurosci 24:3036, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Cohen-Inbar O, Ding D, Sheehan JP: Stereotactic radiosurgery for deep intracranial arteriovenous malformations, part 2: Basal ganglia and thalamus arteriovenous malformations. J Clin Neurosci 24:3742, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Crowley RW, Ducruet AF, McDougall CG, Albuquerque FC: Endovascular advances for brain arteriovenous malformations. Neurosurgery 74 (Suppl 1):S74S82, 2014

    • Search Google Scholar
    • Export Citation
  • 7

    Ding D: Influence of angioarchitecture on management of pediatric intracranial arteriovenous malformations. J Neurointerv Surg 8:e11, 2016

  • 8

    Ding D: Predicting outcomes from radiosurgery for intracranial arteriovenous malformations: effect of embolization, prior hemorrhage, and nidus anatomy. Neurol Sci 36:10251026, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Ding D, Liu KC: Predictive capability of the Spetzler-Martin versus Supplementary Grading Scale for microsurgical outcomes of cerebellar arteriovenous malformations. J Cerebrovasc Endovasc Neurosurg 15:307310, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Ding D, Sheehan JP, Starke RM, Durst CR, Raper DM, Conger JR, : Embolization of cerebral arteriovenous malformations with silk suture particles prior to stereotactic radiosurgery. J Clin Neurosci 22:16431649, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Ding D, Starke RM, Kano H, Lee JY, Mathieu D, Pierce J, : Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations: an international multicenter study. J Neurosurg 126:859871, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Ding D, Starke RM, Kano H, Mathieu D, Huang P, Kondziolka D, : Radiosurgery for cerebral arteriovenous malformations in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)-eligible patients: a multicenter study. Stroke 47:342349, 2016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Ding D, Xu Z, Shih HH, Starke RM, Yen CP, Sheehan JP: Stereotactic radiosurgery for partially resected cerebral arteriovenous malformations. World Neurosurg 85:263272, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Ding D, Xu Z, Starke RM, Yen CP, Shih HH, Buell TJ, : Radiosurgery for cerebral arteriovenous malformations with associated arterial aneurysms. World Neurosurg 87:7790, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Ding D, Xu Z, Yen CP, Starke RM, Sheehan JP: Radiosurgery for cerebral arteriovenous malformations in elderly patients: effect of advanced age on outcomes after intervention. World Neurosurg 84:795804, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Ding D, Xu Z, Yen CP, Starke RM, Sheehan JP: Radiosurgery for unruptured cerebral arteriovenous malformations in pediatric patients. Acta Neurochir (Wien) 157:281291, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Ding D, Yen CP, Starke RM, Xu Z, Sheehan JP: Radiosurgery for ruptured intracranial arteriovenous malformations. J Neurosurg 121:470481, 2014

  • 18

    Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP: Radiosurgery for low-grade intracranial arteriovenous malformations. J Neurosurg 121:457467, 2014

  • 19

    Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP: Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg 118:958966, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP: Radiosurgery for primary motor and sensory cortex arteriovenous malformations: outcomes and the effect of eloquent location. Neurosurgery 73:816824, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Flickinger JC, Kondziolka D, Niranjan A, Lunsford LD: Results of acoustic neuroma radiosurgery: an analysis of 5 years’ experience using current methods. J Neurosurg 119 Suppl:16, 2013

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Flickinger JC, Kondziolka D, Pollock BE, Maitz AH, Lunsford LD: Complications from arteriovenous malformation radiosurgery: multivariate analysis and risk modeling. Int J Radiat Oncol Biol Phys 38:485490, 1997

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Flickinger JC, Pollock BE, Kondziolka D, Lunsford LD: A dose-response analysis of arteriovenous malformation obliteration after radiosurgery. Int J Radiat Oncol Biol Phys 36:873879, 1996

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Hong CS, Peterson EC, Ding D, Sur S, Hasan D, Dumont AS, : Intervention for A randomized trial of unruptured brain arteriovenous malformations (ARUBA) – eligible patients: an evidence-based review. Clin Neurol Neurosurg 150:133138, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Ilyas A, Chen CJ, Ding D, Taylor DG, Moosa S, Lee CC, : Volume-staged versus dose-staged stereotactic radiosurgery outcomes for large brain arteriovenous malformations: a systematic review. J Neurosurg [epub ahead of print January 27, 2017. DOI: 10.3171/2016.9.JNS161571]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Kano H, Kondziolka D, Flickinger JC, Park KJ, Iyer A, Yang HC, : Stereotactic radiosurgery for arteriovenous malformations after embolization: a case-control study. J Neurosurg 117:265275, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Lee CC, Reardon MA, Ball BZ, Chen CJ, Yen CP, Xu Z, : The predictive value of magnetic resonance imaging in evaluating intracranial arteriovenous malformation obliteration after stereotactic radiosurgery. J Neurosurg 123:136144, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Mokin M, Dumont TM, Levy EI: Novel multimodality imaging techniques for diagnosis and evaluation of arteriovenous malformations. Neurol Clin 32:225236, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Moosa S, Chen CJ, Ding D, Lee CC, Chivukula S, Starke RM, : Volume-staged versus dose-staged radiosurgery outcomes for large intracranial arteriovenous malformations. Neurosurg Focus 37(3):E18, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Nagy G, Rowe JG, Radatz MW, Hodgson TJ, Coley SC, Kemeny AA: A historical analysis of single-stage gamma knife radiosurgical treatment for large arteriovenous malformations: evolution and outcomes. Acta Neurochir (Wien) 154:383394, 2012

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    OʼConnor TE, Friedman WA: Magnetic resonance imaging assessment of cerebral arteriovenous malformation obliteration after stereotactic radiosurgery. Neurosurgery 73:761766, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Oermann EK, Ding D, Yen CP, Starke RM, Bederson JB, Kondziolka D, : Effect of prior embolization on cerebral arteriovenous malformation radiosurgery outcomes: a case-control study. Neurosurgery 77:406417, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Pan DHC, Guo WY, Chung WY, Shiau CY, Chang YC, Wang LW: Gamma knife radiosurgery as a single treatment modality for large cerebral arteriovenous malformations. J Neurosurg 93 (3 Suppl 3):113119, 2000

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Patibandla MR, Ding D, Kano H, Xu Z, Lee JYK, Mathieu D, : Stereotactic radiosurgery for Spetzler-Martin Grade IV and V arteriovenous malformations: an international multicenter study. J Neurosurg [epub ahead of print September 8, 2017. DOI: 10.3171/2017.3.JNS162635]

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Patibandla MR, Ding D, Xu Z, Sheehan JP: Stereotactic radiosurgery for pediatric high-grade brain arteriovenous malformations: our experience and review of literature. World Neurosurg 102:613622, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Pollock BE, Kondziolka D, Flickinger JC, Patel AK, Bissonette DJ, Lunsford LD: Magnetic resonance imaging: an accurate method to evaluate arteriovenous malformations after stereotactic radiosurgery. J Neurosurg 85:10441049, 1996

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Pollock BE, Link MJ, Stafford SL, Garces YI, Foote RL: Stereotactic radiosurgery for arteriovenous malformations: the effect of treatment period on patient outcomes. Neurosurgery 78:499509, 2016

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Przybylowski CJ, Ding D, Starke RM, Yen CP, Quigg M, Dodson B, : Seizure and anticonvulsant outcomes following stereotactic radiosurgery for intracranial arteriovenous malformations. J Neurosurg 122:12991305, 2015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:476483, 1986

  • 40

    Starke RM, Ding D, Kano H, Mathieu D, Huang PP, Feliciano C, : International multicenter cohort study of pediatric brain arteriovenous malformations. Part 2: Outcomes after stereotactic radiosurgery. J Neurosurg Pediatr 19:136148, 2017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Starke RM, Kano H, Ding D, Lee JY, Mathieu D, Whitesell J, : Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. J Neurosurg 126:3644, 2017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    Starke RM, Sheehan JP, Ding D, Liu KC, Kondziolka D, Crowley RW, : Conservative management or intervention for unruptured brain arteriovenous malformations. World Neurosurg 82:e668e669, 2014

    • Search Google Scholar
    • Export Citation
  • 43

    Starke RM, Yen CP, Ding D, Sheehan JP: A practical grading scale for predicting outcome after radiosurgery for arteriovenous malformations: analysis of 1012 treated patients. J Neurosurg 119:981987, 2013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Steiner L, Lindquist C, Adler JR, Torner JC, Alves W, Steiner M: Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg 77:18, 1992

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Steiner L, Leksell L, Greitz T, Forster DM, Backlund EO: Stereotaxic radiosurgery for cerebral arteriovenous malformations. Report of a case. Acta Chir Scand 138:459464, 1972

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    Valle RD, Zenteno M, Jaramillo J, Lee A, De Anda S: Definition of the key target volume in radiosurgical management of arteriovenous malformations: a new dynamic concept based on angiographic circulation time. J Neurosurg 109 Suppl:4150, 2008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47

    Yang I, Sughrue ME, Han SJ, Aranda D, Pitts LH, Cheung SW, : A comprehensive analysis of hearing preservation after radiosurgery for vestibular schwannoma: clinical article. J Neurosurg 119 Suppl:851859, 2013

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Yen CP, Ding D, Cheng CH, Starke RM, Shaffrey M, Sheehan J: Gamma Knife surgery for incidental cerebral arteriovenous malformations. J Neurosurg 121:10151021, 2014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 608 0 0
Full Text Views 460 160 16
PDF Downloads 272 71 3
EPUB Downloads 0 0 0