Radiosurgery for ruptured intracranial arteriovenous malformations

Clinical article

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Object

Ruptured intracranial arteriovenous malformations (AVMs) are at a significantly greater risk for future hemorrhage than unruptured lesions, thereby necessitating treatment in the majority of cases. In a retrospective, single-center study, the authors describe the outcomes after radiosurgery in a large cohort of patients with ruptured AVMs.

Methods

From an institutional review board–approved, prospectively collected AVM radiosurgery database, the authors identified all patients with a history of AVM rupture. They analyzed obliteration rates in all patients in whom radiological follow-up data were available (n = 639). However, to account for the latency period associated with radiosurgery, only those patients with more than 2 years of radiological follow-up and those with earlier AMV obliteration were included in the analysis of prognostic factors related to obliteration and complications. This resulted in a cohort of 565 patients with ruptured AVMs for whom data were analyzed; these patients had a median radiological follow-up of 57 months and a median age of 29 years. Twenty-one percent of the patients underwent preradiosurgery embolization. The median volume and prescription dose were 2.1 cm3 and 22 Gy, respectively. The Spetzler-Martin grade was III or higher in 56% of patients, the median radiosurgery-based AVM score was 1.08, and the Virginia Radiosurgery AVM Scale (RAS) score was 3 to 4 points in 44%. Survival and regression analyses were performed to determine obliteration rates over time and predictors of obliteration and complications.

Results

In the overall population of 639 patients with ruptured AVMs, the obliteration rate was 11.1% based on MRI only (71 of 639 patients), 56.0% based on angiography (358 of 639), and 67.1% based on combined modalities (429 of 639 patients). In the cohort of patients with 2 years of follow-up or an earlier AVM obliteration, the cumulative obliteration rate was 76% and the actuarial obliteration rates were 41% and 64% at 3 and 5 years, respectively. Multivariate analysis identified the absence of preradiosurgery embolization (p < 0.001), increased prescription dose (p = 0.001), the presence of a single draining vein (p = 0.046), no postradiosurgery-related hemorrhage (p = 0.007), and lower Virginia RAS score (p = 0.020) as independent predictors of obliteration. The annual risk of a hemorrhage occurring during the latency period was 2.0% and the rate of hemorrhage-related morbidity and mortality was 1.6%. Multivariate analysis showed that decreased prescription dose (p < 0.001) and multiple draining veins (p = 0.003) were independent predictors of postradiosurgery hemorrhage. The rates of symptomatic and permanent radiation-induced changes were 8% and 2.7%, respectively. In the multivariate analysis, a single draining vein (p < 0.001) and higher Virginia RAS score (p = 0.005) were independent predictors of radiation-induced changes following radiosurgery.

Conclusions

Radiosurgery effectively treats ruptured AVMs with an acceptably low risk-to-benefit ratio. For patients with ruptured AVMs, favorable outcomes are more likely when preradiosurgical embolization is avoided and a higher prescription dose can be delivered.

Abbreviations used in this paper:AVM = arteriovenous malformation; DSA = digital subtraction angiography; RAS = Radiosurgery AVM Scale; RBAS = radiosurgery-based AVM score; RIC = radiation-induced change.

Object

Ruptured intracranial arteriovenous malformations (AVMs) are at a significantly greater risk for future hemorrhage than unruptured lesions, thereby necessitating treatment in the majority of cases. In a retrospective, single-center study, the authors describe the outcomes after radiosurgery in a large cohort of patients with ruptured AVMs.

Methods

From an institutional review board–approved, prospectively collected AVM radiosurgery database, the authors identified all patients with a history of AVM rupture. They analyzed obliteration rates in all patients in whom radiological follow-up data were available (n = 639). However, to account for the latency period associated with radiosurgery, only those patients with more than 2 years of radiological follow-up and those with earlier AMV obliteration were included in the analysis of prognostic factors related to obliteration and complications. This resulted in a cohort of 565 patients with ruptured AVMs for whom data were analyzed; these patients had a median radiological follow-up of 57 months and a median age of 29 years. Twenty-one percent of the patients underwent preradiosurgery embolization. The median volume and prescription dose were 2.1 cm3 and 22 Gy, respectively. The Spetzler-Martin grade was III or higher in 56% of patients, the median radiosurgery-based AVM score was 1.08, and the Virginia Radiosurgery AVM Scale (RAS) score was 3 to 4 points in 44%. Survival and regression analyses were performed to determine obliteration rates over time and predictors of obliteration and complications.

Results

In the overall population of 639 patients with ruptured AVMs, the obliteration rate was 11.1% based on MRI only (71 of 639 patients), 56.0% based on angiography (358 of 639), and 67.1% based on combined modalities (429 of 639 patients). In the cohort of patients with 2 years of follow-up or an earlier AVM obliteration, the cumulative obliteration rate was 76% and the actuarial obliteration rates were 41% and 64% at 3 and 5 years, respectively. Multivariate analysis identified the absence of preradiosurgery embolization (p < 0.001), increased prescription dose (p = 0.001), the presence of a single draining vein (p = 0.046), no postradiosurgery-related hemorrhage (p = 0.007), and lower Virginia RAS score (p = 0.020) as independent predictors of obliteration. The annual risk of a hemorrhage occurring during the latency period was 2.0% and the rate of hemorrhage-related morbidity and mortality was 1.6%. Multivariate analysis showed that decreased prescription dose (p < 0.001) and multiple draining veins (p = 0.003) were independent predictors of postradiosurgery hemorrhage. The rates of symptomatic and permanent radiation-induced changes were 8% and 2.7%, respectively. In the multivariate analysis, a single draining vein (p < 0.001) and higher Virginia RAS score (p = 0.005) were independent predictors of radiation-induced changes following radiosurgery.

Conclusions

Radiosurgery effectively treats ruptured AVMs with an acceptably low risk-to-benefit ratio. For patients with ruptured AVMs, favorable outcomes are more likely when preradiosurgical embolization is avoided and a higher prescription dose can be delivered.

Traditionally, intracranial arteriovenous malformations (AVMs) most commonly presented with intracerebral hemorrhage due to AVM rupture.29 With the increasingly widespread availability of advanced neuroimaging modalities, the ratio of ruptured to unruptured AVMs at the time of diagnosis is decreasing.6 Nonetheless, intracerebral hemorrhage remains the most devastating consequence of an untreated AVM.5 Initial studies regarding the natural history of AVMs did not report a substantial difference between the long-term hemorrhage rates of ruptured and unruptured AVMs.12,35 However, a number of recent studies have demonstrated significant differences between the hemorrhage risks of the two cohorts.8,13,38,46 Stapf et al. have reported an annual hemorrhage risk of 0.9% for patients harboring unruptured, superficially located AVMs with a component of superficial venous drainage, whereas it was 34.4% for patients harboring ruptured, deep-seated AVMs with exclusive deep venous drainage.46

The finding that the risk of recurrent hemorrhage in patients with ruptured AVMs is higher than the risk of initial hemorrhage in those with unruptured AVMs has resulted in a tendency to intervene more aggressively in individuals with a history of hemorrhage. Due to the complex nature of AVMs and the wide variation in their angioarchitecture, their treatment is ideally coordinated by a multidisciplinary cerebrovascular team with expertise in microsurgery, endovascular embolization, and radiosurgery.37 While each of the aforementioned treatment approaches, alone and in combination, has its own unique merits and disadvantages, radiosurgery is the least invasive. Since the benefits and risks of radiosurgery manifest in a delayed manner, its role in the specific management of ruptured AVMs, which carry a particularly high risk of rehemorrhage, remains poorly defined. We present our experience with radiosurgery for ruptured AVMs.

Methods

Patient Population

Utilizing a prospective, institutional review board–approved database of approximately 1400 patients with AVM treated with Gamma Knife radiosurgery at the University of Virginia over a 20-year span, from 1989 to 2009, we excluded all patients without radiological follow-up, all patients with unruptured AVMs, and all patients treated with volume-staged radiosurgery. The remaining 639 patients, classified as Cohort A, had ruptured AVMs and radiological follow-up of any duration. In an attempt to account for the latency of successes and complications typically associated with radiosurgery, another cohort, Cohort B, of patients with a minimum of 2 years of radiological follow-up was defined, and this group of patients had 465 ruptured AVMs and the minimum of 2 years of radiological follow-up. Finally, to optimize the power of statistical analyses used to identify factors associated with AVM obliteration, all patients with less than 2 years of radiological follow-up but in whom complete AVM obliteration had been documented were included in Cohort B, yielding 565 patients for statistical regression analysis, and this group was classified Cohort C. Figure 1 shows the composition and the exclusion/inclusion criteria for each of the 3 cohorts.

Fig. 1.
Fig. 1.

Flow chart of patients included for statistical analysis. Three patient cohorts—Cohorts A, B, and C—were selected from an initial institutional AVM radiosurgery database composed of 1400 patients. Data from Cohorts A and B were subjected to a Kaplan-Meier analysis only. Data from Cohort C were subjected to Cox proportional hazards and logistic regression analyses as well as Kaplan-Meier analysis.

In Cohort C, the number of males and females was 292 (51.7%) and 273 (48.3%), respectively. The median age was 28.8 years, with 133 pediatric patients (23.5%) under the age of 18 years. Preradiosurgery microsurgical resection of the AVMs was performed in 98 cases (17.3%) and preradiosurgery embolization was performed in 121 cases (21.4%). Seizure accompanied hemorrhagic presentation in 21 (3.7%) of the 565 patients. The patient population of Cohort C is detailed in Table 1.

TABLE 1:

Patient characteristics of Cohort C*

CharacteristicValue (%)
sex
 male292 (51.7)
 female273 (48.3)
age (yrs)
 mean31.6
 median28.8
 range3.7–81.1
pediatric patients age <18 yrs133 (23.5)
pre-RS embol121 (21.4)
pre-RS microsurgical resection98 (17.3)
pre-RS seizures21 (3.7)

embol = embolization; RS = radiosurgery.

Values represent the number (%) of patients.

Radiosurgery Parameters and AVM Characteristics

Our institution's Gamma Knife radiosurgery technique has been previously described in detail.50 Prior to 1991, only digital subtraction angiography (DSA) was used to delineate an AVM's nidus. Since 1991, MRI has been routinely used in conjunction with DSA to optimize spatial accuracy for treatment planning. Dose planning was initially performed with the Kula software, from 1989 until June 1994, but this has since been replaced with the GammaPlan software (Elekta AB). In Cohort C, the median treatment parameters for the first radiosurgery session were as follows: AVM volume 2.1 cm3, prescription dose 22 Gy, maximum dose 40 Gy, isodose line 50%, and number of isocenters 2. With deep location defined as basal ganglia, thalamus, or brainstem, AVM location was superficial in 361 patients (63.9%) and deep in 204 patients (36.1%). The venous drainage pattern was superficial only in 188 patients (33.3%) and deep in 377 patients (66.7%). There was a single draining vein in 367 patients (65.0%), and multiple draining veins in 198 patients (35.0%). Associated aneurysms, defined as those on feeding arteries in, or proximal to, the nidus, were present in 32 cases (5.7%) including 13 intranidal aneurysms (2.3%) and 19 perinidal aneurysms (3.4%). The Spetzler-Martin grade, which factors in AVM diameter, superficial or deep venous drainage, and eloquence of involved cortex, was I in 71 patients (12.6%), II in 179 patients (31.7%), III in 252 patients (44.6%), IV in 63 patients (11.1%), and V in 0 patients.44 The radiosurgery-based AVM score (RBAS), which factors in patient age, AVM volume, and superficial or deep location, was < 1.00 in 235 patients (41.6%), 1.00–1.50 in 231 patients (40.9%), 1.51–2.00 in 79 patients (14.0%), and > 2.00 in 20 patients (3.5%) (median RBAS 1.08).55 Accounting for history of hemorrhage prior to radiosurgery, eloquence of location, and AVM volume, the recently described Virginia Radiosurgery AVM Scale (RAS) was 1 in 84 patients (14.9%), 2 in 234 patients (41.4%), 3 in 145 patients (25.7%), and 4 in 102 patients (18.0%).49 The AVM attributes and treatment parameters for Cohort C are detailed in Table 2.

TABLE 2:

Summary of Cohort C AVM characteristics and treatment parameters

CharacteristicValue (%)
location
 superficial361 (63.9)
 deep*204 (36.1)
location
 noneloquent178 (31.5)
 eloquent387 (68.5)
venous drainage pattern
 superficial188 (33.3)
 deep377 (66.7)
draining veins
 single367 (65.0)
 multiple198 (35.0)
maximum diameter in cm
 mean2.1
 median2.0
 range0.2–5.5
volume in cm3
 mean3.0
 median2.1
 range0.1–33
no. of associated aneurysms
 intranidal13 (2.3)
 perinidal19 (3.4)
prescription dose in Gy
 mean21.7
 median22
 range8–36
maximum dose in Gy
 mean38.8
 median40
 range20–60
isodose in %
 mean57.4
 median50
 range30–90
no. of isocenters
 mean2.5
 median2.0
 range1–14
Spetzler–Martin grade
 I71 (12.6)
 II179 (31.7)
 III252 (44.6)
 IV63 (11.1)
RBAS
 mean1.11
 median1.08
 range0.21–3.90
 <1.00235 (41.6)
 1.00–1.50231 (40.9)
 1.51–2.0079 (14.0)
 >2.0020 (3.5)
Virginia RAS score
 184 (14.9)
 2234 (41.4)
 3145 (25.7)
 4102 (18.0)

Deep location includes basal ganglia, thalamus, and brainstem.

Values represent the number (%) of lesions.

Repeat Radiosurgery

If the AVM nidus remained patent 3 years after radiosurgery, repeat radiosurgery was considered. In Cohort C, repeat radiosurgery was performed for incompletely obliterated AVMs in 92 patients (16.3%) including 1 repeat treatment in 86 patients (15.2%) and 2 repeat treatments in 6 patients (1.1%). For the first repeat radiosurgery session, the treatment parameters were as follows: AVM volume of mean 1.4 cm3, median 1.0 cm3, and range 0.1–5.1 cm3; prescription dose mean 20.9 Gy, median 22 Gy, and range 4–28 Gy; maximum dose mean 36.7 Gy, median 40 Gy, and range 8–50 Gy; isodose line mean 59%, median 50%, and range 48–96%; and number of isocenters mean 2.9, median 2, and range 1–22. For the second repeat radiosurgery, the treatment parameters were as follows: volume mean 0.47 cm3, median 0.34 cm3, and range 0.1–1.2 cm3; prescription dose mean 22.8 Gy, median 23 Gy, and range 20–25 Gy; maximum dose mean 45.7 Gy, median 46 Gy, and range 40–50 Gy; isodose line 50% for all treatments; and number of isocenters mean 5.7, median 4.5, and range 2–11.

Radiological and Clinical Follow-Up

Routine radiological follow-up consisted of an MRI every 6 months for the first 3 years after treatment. Additional imaging, invariably CT or MRI, was performed in cases of neurological decline. Digital subtraction angiography was obtained after an MRI showed complete AVM obliteration. Obliteration was defined on MRI as an absence of flow voids and on DSA as lack of abnormal arteriovenous shunting. Hemorrhage was identified radiologically with or without clinical correlation. Radiation-induced changes (RICs) were defined on MRI as T2-weighted hyperintensities and were classified as symptomatic if the patient experienced concomitant clinical symptoms, most commonly headache, seizure, or focal neurological deficits. The cumulative radiological follow-up of Cohort C was mean 74.5 months (6.2 years), median 57.2 months (4.8 years), and range 5.3–261.6 months (0.4–21.8 years). Since our institution is a tertiary radiosurgery referral center, clinical follow-up was a combination of return appointments and admissions to the University of Virginia Health System clinics and hospital, respectively, and correspondence with outside referring hospitals and with patients' local specialists or primary care physicians. The clinical follow-up in Cohort C was a mean of 84.2 months (7.0 years), median of 72.2 months (6.0 years), and range of 6.2–312.9 months (0.5–26.1 years).

Statistical Analysis

The IBM SPSS version 20 statistical software program was used to perform all analyses. Kaplan-Meier analysis was conducted to calculate time to obliteration and actuarial obliteration rates following radiosurgery. Kaplan-Meier analysis for obliteration was performed for Cohorts A, B, and C. Cox proportional hazards regression analysis was used to determine predictors of obliteration, and logistic regression analysis was used to determine predictors of postradiosurgery hemorrhage and RICs. The variables analyzed were sex, age at the time of radiosurgery, preradiosurgery embolization, AVM volume, AVM location (superficial vs deep and noneloquent vs eloquent), venous drainage pattern (superficial vs deep), number of draining veins (single vs multiple), presence of associated aneurysms, prescription dose, number of isocenters, postradiosurgery hemorrhage, radiological evidence of RICs, Spetzler-Martin grade, RBAS, and Virginia RAS score. Univariate analysis was applied to all variables. For each variable, a hazard ratio (Cox analysis) or odds ratio (logistic analysis) with 95% CI and p value were calculated. Statistical significance was defined as hazard or odds ratio with a 95% CI not including 1.0 and p value less than 0.05. All statistical studies were 2 sided. Multivariate analysis was performed if more than 1 statistically significant predictor was identified in the univariate analysis. The backward likelihood ratio method was used in the multivariate Cox proportional hazards regression analysis. Cox proportional hazards and logistic regression analyses were only performed for data obtained in Cohort C. The annual postradiosurgery hemorrhage rate was defined as the ratio of the number of individual hemorrhage events following radiosurgery to the total number of risk years, which was the time to obliteration or, in AVMs without complete obliteration, the time to last radiological follow-up.

Results

Radiological Outcomes Following Radiosurgery in Cohorts A, B, and C

In Cohort A, the obliteration rate was 11.1% based on MRI only (71 of 639 patients), 56.0% based on DSA (358 of 639 patients), and 67.1% based on combined modalities (429 of 639 patients). The actuarial obliteration rate in Cohort A was 41% at 3 years and 64% at 5 years, with a median time to obliteration of 41.2 months. In Cohort B, the obliteration rate was 12.7% based on MRI only (59 of 465 patients), 58.1% based on DSA (270 of 465 patients), and 70.8% based on combined modalities (329 of 465 patients). The actuarial obliteration rate in Cohort B was 29% at 3 years and 56% at 5 years, with a median time to obliteration of 53.1 months.

In Cohort C, total AVM obliteration was identified on MRI only in 12.6% (71 of 565 patients) and confirmed by DSA in 63.4% (358 of 565 patients) for an overall obliteration rate of 76%. The actuarial rates of obliteration at 3 and 5 years were 41% and 64%, respectively. The median time to obliteration was 41.2 months (range 5.3–261.6 months). The difference between the actuarial obliteration rates of Cohorts A and C was not statistically significant (p = 0.871). However, the difference between the actuarial obliteration rates of Cohorts B and C was significant (p < 0.001). Figure 2 shows the rate of obliteration for ruptured AVMs over time for Cohorts A, B, and C.

Fig. 2.
Fig. 2.

Kaplan-Meier plots demonstrating the obliteration rates over time of ruptured AVMs following radiosurgery in Cohorts A, B, and C. The x axis displays the number of patients remaining at each time interval. The rates of obliteration over time were not significantly different between Cohorts A and C (p = 0.871) but were significantly different between Cohorts B and C (p < 0.001).

Predictors of AVM Obliteration in Cohort C Only

In the univariate Cox proportional hazards regression analysis, we found that the following factors were associated with an increased likelihood of obliteration: no preradiosurgery embolization, decreased volume, increased prescription dose, fewer isocenters, single draining vein, no postradiosurgery hemorrhage, lower Spetzler-Martin grade, lower RBAS, and lower Virginia RAS score. The following factors were determined to be independent predictors of obliteration based on multivariate analysis: no preradiosurgery embolization (p < 0.001), increased prescription dose (p = 0.001), single draining vein (p = 0.046), no postradiosurgery hemorrhage (p = 0.007), and lower Virginia RAS score (p = 0.020). The results of the univariate and multivariate Cox proportional hazards regression analyses are detailed in Table 3.

TABLE 3:

Factors predicting obliteration after radiosurgery*

FactorUnivariate AnalysisMultivariate Analysis
Hazard Ratio95% CIp ValueHazard Ratio95% CIp Value
male sex1.020.845–1.240.819
increased age1.000.996–1.010.624
no pre-RS embol2.321.77–3.04<0.0011.781.35–2.35<0.001
superficial location1.100.900–1.340.356
noneloquent location1.150.939–1.400.178
decreased volume1.211.15–1.27<0.0011.040.970–1.110.293
no associated aneurysms1.460.930–2.280.100
increased prescription dose1.111.09–1.14<0.0011.051.02–1.090.001
fewer isocenters1.121.05–1.200.0011.020.962–1.090.470
superficial venous drainage1.040.852–1.270.694
single draining vein1.401.14–1.720.0011.241.00–1.520.046
no post-RS hem2.211.55–3.15<0.0011.651.20–2.450.007
no RICs1.140.977–1.340.097
lower Spetzler-Martin grade1.261.14–1.40<0.0011.150.992–1.340.064
lower RBAS1.761.41–2.21<0.0011.250.974–1.600.080
lower Virginia RAS score1.531.38–1.70<0.0011.191.03–1.370.020

hem = hemorrhage; — = not applicable.

Boldface indicates statistical significance.

The actuarial obliteration rates of ruptured AVMs without prior embolization were 47% and 71% at 3 and 5 years, respectively. For ruptured AVMs that received preradiosurgery embolization, the actuarial obliteration rates were 22% and 36% at 3 and 5 years, respectively. The obliteration rates for nonembolized AVMs were significantly higher than those for embolized AVMs (p < 0.001). Figure 3 shows the obliteration rates for nonembolized and embolized ruptured AVMs in Cohort C.

Fig. 3.
Fig. 3.

Kaplan-Meier plot demonstrating the radiosurgical obliteration rate of nonembolized and embolized ruptured AVMs over time in Cohort C. The x axis displays the number of ruptured AVMs with and without a history of embolization remaining at each interval.

Postradiosurgery Hemorrhage in Cohort C Only

Following radiosurgery in Cohort C, there were 54 individual hemorrhage events; these were composed of 1 hemorrhage in each of 38 patients and 2 hemorrhages in each of 8 patients. Divided by a total of 2684 risk years, the annual postradiosurgery hemorrhage rate was 2.0%. Postradiosurgery hemorrhage-related morbidity and mortality was observed in 7 (1.2%) and 2 (0.4%) patients, respectively, for a combined hemorrhage-related complication rate of 1.6%. There were 136 patients without AVM obliteration following radiosurgery. Of those nidi that did not undergo radiosurgical obliteration, the 77 nonembolized AVMs had an annual postradiosurgery hemorrhage risk of 1.9% (11 hemorrhages over 589 risk-years), and the 59 embolized AVMs had an annual postradiosurgery hemorrhage risk of 3.5% (15 hemorrhages over 434 risk-years). The hemorrhage risks between embolized and nonembolized patent AVMs were not significantly different (p = 0.561).

In the univariate logistic regression analysis, we identified the factors as being associated with postradiosurgery hemorrhage: preradiosurgery embolization, eloquent location, increased volume, decreased prescription dose, multiple draining veins, higher Spetzler-Martin grade, higher RBAS, and higher Virginia RAS score. Based on multivariate analysis, decreased prescription dose (p < 0.001) and multiple draining veins (p = 0.003) were independent predictors of postradiosurgery hemorrhage. No instances of AVM hemorrhage were observed after total obliteration of the nidus was determined by MRI or DSA. The results of the univariate and multivariate logistic regression analyses are detailed in Table 4.

TABLE 4:

Factors predicting postradiosurgery hemorrhage*

FactorUnivariate AnalysisMultivariate Analysis
Odds Ratio95% CIp ValueOdds Ratio95% CIp Value
female sex1.430.780–2.630.247
decreased age1.010.988–1.030.427
pre-RS embol2.101.10–3.990.0241.060.512–2.200.872
deep location1.540.840–2.830.162
eloquent location2.311.06–5.070.0361.430.521–3.900.489
increased volume1.111.04–1.190.0021.050.929–1.190.439
associated aneurysms2.220.813–6.080.120
decreased prescription dose1.291.17–1.41<0.0011.221.10–1.36<0.001
fewer isocenters1.020.855–1.210.843
deep venous drainage1.030.543–1.970.920
multiple draining veins2.891.56–5.350.0012.641.39–5.010.003
RICs1.440.74–2.810.285
higher Spetzler-Martin grade1.621.11–2.370.0121.200.675–2.140.535
higher RBAS2.061.16–3.640.013
higher Virginia RAS score2.141.52–3.00<0.0011.460.992–2.140.055

Boldface indicates statistical significance.

Radiation-Induced Changes and Cyst Formation Following Radiosurgery in All Cohorts

The radiological presence of postradiosurgery RICs was evident in 166 patients (29.4%) in Cohort C. The time interval following radiosurgery to RIC was as follows: mean 12.3 months, median 9.1 months, and range 3–124 months; the duration of an RIC (from appearance to resolution) was as follows: mean 19.8 months, median 13.5 months, and range 5–128 months. Figure 4 shows the prevalence of RICs over time in Cohort C. The RICs were symptomatic in 45 patients (8.0%) and comprised transient symptoms in 30 patients (5.3%) and permanent symptoms in 15 patients (2.7%). Specifically, symptomatic RIC clinically manifested as headache in 16 patients (2.8%) and focal neurological deficit in 29 patients (5.1%). All 15 patients with permanent symptomatic RIC had new or worsened focal neurological deficits following radiosurgery.

Fig. 4.
Fig. 4.

Kaplan-Meier plot demonstrating the prevalence of RICs over time following radiosurgery in Cohort C. The x axis displays the number of patients remaining at each time interval.

In Cohort A, the rates of cumulative, symptomatic, and permanent RICs were 26.3% (168 of 639 patients), 7.2% (46 of 639 patients), and 2.5% (16 of 639 patients), respectively. In Cohort B, the rates of cumulative, symptomatic, and permanent RICs were 29.5% (137 of 465 patients), 7.7% (36 of 465 patients), and 2.8% (13 of 465 patients), respectively.

Predictors of Postradiosurgery RICs in Cohort C Only

The univariate logistic regression analysis of data obtained from Cohort C identified 2 factors, a single draining vein and higher Virginia RAS score, as being associated with postradiosurgery RICs. Both a single draining vein (p < 0.001) and higher Virginia RAS score (p = 0.018) were also determined to be independent predictors of RICs following radiosurgery in the multivariate analysis. The results of the univariate and multivariate logistic regression analyses are detailed in Table 5. Six patients developed postradiosurgery cysts (1.1%), but none of the cysts were symptomatic nor did they require intervention.

TABLE 5:

Factors predicting RICs following radiosurgery*

FactorUnivariateMultivariate
Odds Ratio95% CIp ValueOdds Ratio95% CIp Value
female sex1.330.912–1.930.139
increased age1.010.994–1.020.399
pre-RS embol1.110.710–1.740.641
superficial location1.190.802–1.760.390
noneloquent location1.050.700–1.570.826
no associated aneurysms1.370.573–3.280.479
increased volume1.050.976–1.120.208
decreased prescription dose1.040.979–1.100.210
more isocenters1.010.907–1.110.918
deep venous drainage1.030.689–1.530.898
single draining vein2.361.54–3.64<0.0012.531.64–3.92<0.001
post-RS hem1.260.733–2.160.405
higher Spetzler–Martin grade1.010.806–1.260.960
higher RBAS1.220.806–1.850.345
higher Virginia RAS score1.271.04–1.550.0181.341.09–1.640.005

Boldface indicates statistical significance.

Clinical Outcomes Following Radiosurgery in Cohort C Only

No patients presenting with seizures experienced worsening of seizures following radiosurgery. Eight patients had decreased seizure frequency (1.4%) and 12 patients were free of seizures (2.1%) after radiosurgery. New-onset postradiosurgery-related seizures were seen in 3 patients (0.5%). Clinical improvement was seen in 70 patients (12.4%). Radiosurgery-related morbidity was observed in a total of 73 patients (12.9%), with deterioration being temporary in 44 patients (7.8%) and permanent in 29 patients (5.1%). By the time of the last clinical follow-up, 5 patients had died, and 2 of these deaths (0.4%) were attributable to postradiosurgery hemorrhage. The cumulative rate of permanent morbidity and mortality following radiosurgery was 5.5%.

Discussion

It has become increasingly evident that the hemorrhage risk associated with ruptured AVMs is significantly higher than it is with unruptured lesions. Pollock et al. have reported an annual hemorrhage risk of 7.5% in patients with ruptured AVMs compared with an annual risk of 1.9% in patients with unruptured AVMs.38 In a study of 622 AVM patients, Stapf et al. subsequently identified hemorrhagic presentation as being a significant predictor of AVM hemorrhage (HR 5.4, 95% CI 2.6–11.0).46 Most recently, Gross and Du performed a meta-analysis of over 3900 patients with approximately 18,000 years of follow-up and calculated that the annual hemorrhage risks for ruptured and unruptured AVMs were 4.5% and 2.2%, respectively.13 Prospective, multicenter studies such as A Randomized Trial of Unruptured Brain AVMs (ARUBA) have been undertaken to shed light on the risks and benefits of intervention compared with conservative management of unruptured AVMs, which is currently the subject of much debate.7,9,11,31,47,48 However, the risk of intervention in cases of ruptured AVMs is less controversial due to the relatively higher prospective risk of hemorrhage and the morbidity and mortality associated with AVM rupture.35

Microsurgical Resection of Ruptured AVMs

Most microsurgical AVM series include the data from ruptured and unruptured lesions without a clear distinction between the surgical outcomes from the 2 cohorts.14,17 Additionally, the Spetzler-Martin grading system, which is the most widely used classification scheme for AVMs, does not account for preoperative hemorrhage.44 Ruptured AVMs are generally considered more amenable to microsurgical resection than unruptured ones because increased surgical access to the nidus has been facilitated by AVM hemorrahge.27 Posthemorrhagic gliosis, encephalomalacia, and cavitation may further ease surgical approaches to ruptured lesions. However, these changes do not occur in the immediate period following AVM rupture, thereby making it prudent to wait 2–4 weeks after a hemorrhage before pursuing surgical intervention. In instances in which a hematoma is exerting significant mass effect, decompression may be necessary to avert an intracranial pressure crisis. While decompression does not typically simultaneously require AVM resection, there are times when hematoma evacuation leads one into the nidus.

Lawton et al. compared the microsurgical outcomes for unruptured and ruptured AVMs in 224 patients.27 Of the 120 ruptured AVMs, 38 (32%) were at least 3 cm in size, 68 (57%) were in eloquent locations, and 55 (46%) were at least Spetzler-Martin Grade III. The mean modified Rankin Scale scores for the ruptured-AVM group at presentation and at discharge were 2.8 and 1.9, respectively, and neurological morbidity rate was 19% according to the same scale. Based on modified Rankin Scale scores, patients with ruptured AVMs were more likely to experience neurological improvement than those with unruptured AVM (p < 0.001), but individuals with unruptured AVM still had higher modified Rankin Scale scores at follow-up (p = 0.048) because of the poorer initial neurological condition in patients with ruptured AVM (p < 0.001). To account for the additional risk of resecting an unruptured AVM, the same group devised a supplementary grading scale, which predicts microsurgical AVM outcomes based on patient age, history of AVM rupture, and compactness of the nidus.28

Endovascular Embolization of Ruptured AVMs

Stemer et al. reported on 21 patients with ruptured AVMs who underwent acute embolization using Onyx (ev3) at a median interval of 4 days following the ictus.51 Complete occlusion was achieved in 52% of the patients. However, 29% and 5% of the ruptured AVMs were subsequently treated with resection and radiosurgery, respectively, and the intraprocedural complication and posttreatment mortality rates were each 10%. The procedural complications were asymptomatic and the deaths were unrelated to AVM treatment. There were no reports of recurrent AVM hemorrhage following acute embolization. Nonetheless, the study remains limited by a relatively small cohort size and the short duration of angiographic follow-up (median 7.5 months), which was available in only 12 patients. The role of acute embolization as a means of protecting ruptured AVMs from subsequent hemorrhage remains poorly defined.

For small, compact AVMs, embolization with permanent embolic agents may achieve complete obliteration, although cure rates range widely from 10% to 50% depending on the selectivity of the study and the aggressiveness of the neurointerventionalists.25,33,36,41,54 However, the combined rate of embolization-induced morbidity and mortality is up to 10% in some series, which is considerable given the relatively low rate of total obliteration.25,41,54 Without a conclusively proven benefit in the acute setting for ruptured AVMs as a stand-alone procedure, the role of endovascular embolization remains primarily a neoadjuvant treatment to facilitate subsequent definitive radiosurgical or microsurgical AVM obliteration. Preoperative embolization was used in 52% of the ruptured AVMs in the aforementioned microsurgery series by Lawton et al.27 The efficacy of endovascular embolization following radiosurgery whose goal is to protect the vascular structures at particularly high risk for rupture during the latency period is currently unknown.

Radiosurgery for Ruptured AVMs

Since the outcomes, both beneficial and adverse, of radiosurgery manifest in a delayed manner, radiosurgical treatment of ruptured AVMs is generally not undertaken in the acute or early subacute setting. Intracerebral hemorrhage is an inherently devastating clinicopathological process, and an AVM rupture is no exception.6,16 Patients should be medically and neurologically stabilized according to currently established guidelines.32 Due to the length of time over which radiosurgery-induced obliteration occurs, treatment should only be offered to those patients whose recovery from AVM hemorrhage is such that they will not succumb to other medical comorbidities prior to realizing any potential benefit from radiosurgery. Furthermore, blood products from a hemorrhage may obscure the borders of the nidus and decrease the accuracy of radiosurgical targeting of the nidus. Some authors have even argued that hemosiderin can adversely radiosensitize normal brain tissue.45 For these reasons, at our institution we typically wait 6–12 weeks from the ictus to treat a ruptured AVM.

The overall obliteration rate of ruptured AVMs ranged from 67% in Cohort A to 76% in Cohort C. The obliteration and complication rates varied slightly depending upon the minimum follow-up criteria used to define each of the 3 cohorts. Preradiosurgery embolization was an independent predictor of a diminished obliteration rate (p < 0.001). The negative impact of embolization on radiosurgery has been evidenced by radiosurgical outcomes recorded at other institutions as well as from our own, although the reasons for the lower obliteration rates are poorly understood.2,10,18,30,39,43 Attenuation or scattering of radiation beams by embolic material has been proposed as a possible mechanism, although recent in vitro studies by Bing et al. did not support this hypothesis.2,3 Alternative explanations include increased difficulty of radiosurgical targeting, decrease in radiosensitivity with concomitant increase in angiogenic activity, and recanalization of the nidus following embolization.1,26,34,52,53 Our findings are not meant to discourage the use of preradiosurgery embolization but rather to support a relatively conservative endovascular approach prior to planned radiosurgical AVM treatment. Nevertheless, 21% of the AVMs in the present series were embolized prior to radiosurgery. We currently reserve embolization for reducing the size of large or diffuse lesions to increase the efficiency of radiosurgical targeting, obliterating high-flow feeding pedicles, and occluding perinidal or intranidal aneurysms or arteriovenous shunts.

Drainage of an AVM into a single vein likely indicates a relatively compact nidus, which facilitates radiosurgery targeting. In our series, AVMs with a single draining vein had higher rates of obliteration (p = 0.046), but they were also more likely to be associated with an RIC (p < 0.001). In Cohort C, the cumulative rate of postradiosurgery RICs was 29%, and of these 21% were asymptomatic, 5% were transiently symptomatic, and 3% were permanent. The Virginia RAS was derived from over 1000 AVM patients treated with radiosurgery at our institution with the goal of accurately predicting AVM radiosurgery outcomes.49 In this study of ruptured AVMs, a lower Virginia RAS score was independently associated with successful obliteration (p = 0.020), whereas a higher Virginia RAS score was independently associated with postradiosurgery RICs (p = 0.018). We are currently in the process of further studying the Virginia RAS in relation to AVM radiosurgery outcomes data from additional institutions.

Just as singular venous drainage likely correlates to compact nidus, by corollary, diffuse AVMs are more apt to have multiple draining veins. Given our finding that AVMs with multiple draining veins were more likely to have postradiosurgery hemorrhage (p = 0.003), we hypothesize that ruptured diffuse AVMs may be at higher risk for latency-period hemorrhage than compact ones. The annual postradiosurgery hemorrhage rate was 2.0% with a 1.6% rate of hemorrhage-related morbidity (1.2%) and mortality (0.4%) during the latency period. Postradiosurgery hemorrhage was an independent negative predictor of obliteration (p = 0.007). Higher prescription doses were more likely to result in AVM obliteration (p = 0.001), whereas AVMs receiving lower prescription doses were more apt to latency-period hemorrhage (p < 0.001). Incompletely obliterated AVMs retain a risk for rupture, and some groups have suggested that partial treatment may lead to degeneration of the nidus such that the hemorrhage risk from a partially obliterated AVM exceeds that of an untreated one.15 However, when comparing the postradiosurgery hemorrhage risk of the AVMs in our study to the natural history hemorrhage rates reported for the same lesions, radiosurgical treatment may provide a partial degree of protection to AVMs prior to complete obliteration.13,38,46,56 The mechanism of radiosurgery-induced AVM stabilization could be related to progressive flow reduction by intimal hyperplasia and vascular thrombosis.4,42 Preradiosurgery embolization did not significantly reduce the postradiosurgery hemorrhage risk of AVMs during the latency period following radiosurgery (p = 0.561), although this study was neither designed nor powered to detect such a difference.

Study Limitations

Despite boasting a substantial number of patients with long-term radiological and clinical follow-up, our results remain limited by the selection biases associated with a retrospective, single-center study. Because of the inherent nature of the delayed obliteration that occurs following radiosurgery, patients presenting with poor neurological condition due to AVM rupture were significantly more likely to undergo rapid surgical intervention or conservative palliation than those without disabling neurological deficits. An additional bias of our study lies in the exclusion of patients with less than 2 years of radiological follow-up, except for those with AVM obliteration, which may result in an artificially elevated obliteration rate. This approach was taken to account for the latency of beneficial as well as adverse effects observed following radiosurgery of AVMs. However, to account for this bias, we have included, in the appropriate subsections of the results, the rates of obliteration and RIC for all patients regardless of radiological follow-up (Cohort A) and for patients with at least 2 years radiological follow-up only (Cohort B). Another weakness is the lack of angiographic confirmation of obliteration in 13% of patients for whom the only neuroimaging documentation of obliteration was MRI. While DSA is the gold standard for evaluating AVM obliteration, Pollock et al. have reported the sensitivity, specificity, and negative predictive value of MRI compared with DSA to be 80%, 100%, and 91%, respectively.40 The use of MRI as the sole modality to document obliteration has been reported by authors from another tertiary radiosurgery referral center in a large recent series of radiosurgery in AVMs .19–24

As to the AVMs that received preradiosurgery embolization in the present study, we do not have specific information regarding the goal of embolization in each case, nor do we know if the goal of embolization was achieved in each case. The lack of these data may affect our perspective on the role of embolization in the management of AVMs, especially in relation to radiosurgery. With respect to clinical follow-up, it was not adequately detailed so that a standard clinical outcome score, such as the Glasgow Outcome Scale or modified Rankin Scale score, could be extrapolated for each patient. Because of the way a tertiary referral center for AVM radiosurgery functions, some of the follow-up information we obtained was by indirect means, through referring physicians or hospitals. Additionally, the long period over which the patients were treated (20 years) further contributed to the difficulty in acquiring detailed clinical follow-up. Therefore, we could not assign a quantifiable outcome score to all patients.

Conclusions

A growing body of evidence in the literature supports the notion that the risk of recurrent hemorrhage from a ruptured AVM is much higher than the risk of initial hemorrhage from an unruptured AVM. Thus, the pressure on cerebrovascular neurosurgeons to completely obliterate an AVM with previous hemorrhage is relatively high. Radiosurgery offers an effective, minimally invasive therapeutic option for patients with ruptured AVMs and the rate of complete obliteration is reasonable. Given the natural history of ruptured AVMs, radiosurgery is associated with a comparatively low risk of treatment-related morbidity. A higher radiation dose and no prior embolization portend a greater chance for radiosurgical obliteration.

Disclosure

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 to the study and manuscript preparation include the following. Conception and design: Sheehan, Ding. Acquisition of data: Ding, Yen. Analysis and interpretation of data: all authors. Drafting the article: Ding, Yen, Starke. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Sheehan. Statistical analysis: Ding, Xu.

References

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Article Information

Address correspondence to: Jason Sheehan, M.D., Ph.D., Department of Neurological Surgery, University of Virginia Health System, P.O. Box 800212, Charlottesville, VA 22908. email: jps2f@virginia.edu.

Please include this information when citing this paper: published online March 21, 2014; DOI: 10.3171/2014.2.JNS131605.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flow chart of patients included for statistical analysis. Three patient cohorts—Cohorts A, B, and C—were selected from an initial institutional AVM radiosurgery database composed of 1400 patients. Data from Cohorts A and B were subjected to a Kaplan-Meier analysis only. Data from Cohort C were subjected to Cox proportional hazards and logistic regression analyses as well as Kaplan-Meier analysis.

  • View in gallery

    Kaplan-Meier plots demonstrating the obliteration rates over time of ruptured AVMs following radiosurgery in Cohorts A, B, and C. The x axis displays the number of patients remaining at each time interval. The rates of obliteration over time were not significantly different between Cohorts A and C (p = 0.871) but were significantly different between Cohorts B and C (p < 0.001).

  • View in gallery

    Kaplan-Meier plot demonstrating the radiosurgical obliteration rate of nonembolized and embolized ruptured AVMs over time in Cohort C. The x axis displays the number of ruptured AVMs with and without a history of embolization remaining at each interval.

  • View in gallery

    Kaplan-Meier plot demonstrating the prevalence of RICs over time following radiosurgery in Cohort C. The x axis displays the number of patients remaining at each time interval.

References

  • 1

    Achrol ASGuzman RVarga MAdler JRSteinberg GKChang SD: Pathogenesis and radiobiology of brain arteriovenous malformations: implications for risk stratification in natural history and posttreatment course. Neurosurg Focus 26:5E92009

    • Search Google Scholar
    • Export Citation
  • 2

    Andrade-Souza YMRamani MScora DTsao MNterBrugge KSchwartz ML: Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery 60:4434522007

    • Search Google Scholar
    • Export Citation
  • 3

    Bing FDoucet RLacroix FBahary JPDarsaut TRoy D: Liquid embolization material reduces the delivered radiation dose: clinical myth or reality?. AJNR Am J Neuroradiol 33:3203222012

    • Search Google Scholar
    • Export Citation
  • 4

    Chang SDShuster DLSteinberg GKLevy RPFrankel K: Stereotactic radiosurgery of arteriovenous malformations: pathologic changes in resected tissue. Clin Neuropathol 16:1111161997

    • Search Google Scholar
    • Export Citation
  • 5

    Choi JHMast HSciacca RRHartmann AKhaw AVMohr JP: Clinical outcome after first and recurrent hemorrhage in patients with untreated brain arteriovenous malformation. Stroke 37:124312472006

    • Search Google Scholar
    • Export Citation
  • 6

    Choi JHMohr JP: Brain arteriovenous malformations in adults. Lancet Neurol 4:2993082005

  • 7

    Cockroft KM: Unruptured brain arteriovenous malformations should be treated conservatively: no. Stroke 38:331033112007

  • 8

    da Costa LWallace MCTer Brugge KGO'Kelly CWillinsky RATymianski M: The natural history and predictive features of hemorrhage from brain arteriovenous malformations. Stroke 40:1001052009

    • Search Google Scholar
    • Export Citation
  • 9

    Davis SMDonnan GA: Unruptured brain arteriovenous malformations: another asymptomatic conundrum. Stroke 38:33122007

  • 10

    Ding DYen CPXu ZStarke RMSheehan JP: Radiosurgery for patients with unruptured intracranial arteriovenous malformations. Clinical article. J Neurosurg 118:9589662013

    • Search Google Scholar
    • Export Citation
  • 11

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