Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations

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Object

The purpose of this study was to define the outcomes and risks of stereotactic radiosurgery (SRS) for Spetzler-Martin (SM) Grade III arteriovenous malformations (AVMs).

Methods

Between 1987 and 2009, SRS was performed in 474 patients with SM Grade III AVMs. The AVMs were categorized by scoring the size (S), drainage (D), and location (L): IIIa was a small AVM (S1D1L1, N = 282); IIIb was a medium/deep AVM (S2D1L0, N = 44); and IIIc was a medium/eloquent AVM (S2D0L1, N = 148). The median target volume was 3.8 ml (range 0.1–26.3 ml) and the margin dose was 20 Gy (range 13–25 Gy). Eighty-one patients (17%) underwent prior embolization, and 58 (12%) underwent prior resection.

Results

At a mean follow-up of 89 months, the total obliteration rates documented by angiography or MRI for all SM Grade III AVMs increased from 48% at 3 years to 69% at 4 years, 72% at 5 years, and 77% at 10 years. The SM Grade IIIa AVMs were more likely to obliterate than other subgroups. The cumulative rate of hemorrhage was 2.3% at 1 year, 4.4% at 2 years, 5.5% at 3 years, 6.4% at 5 years, and 9% at 10 years. The SM Grade IIIb AVMs had a significantly higher cumulative rate of hemorrhage. Symptomatic adverse radiation effects were detected in 6%.

Conclusions

Treatment with SRS was an effective and relatively safe management option for SM Grade III AVMs. Although patients with residual AVMs remained at risk for hemorrhage during the latency interval, the cumulative 10-year 9% hemorrhage risk in this series may represent a significant reduction compared with the expected natural history.

Abbreviations used in this paper:ARE = adverse radiation effect; AVM = arteriovenous malformation; HR = hazard ratio; SM = Spetzler-Martin; SRS = stereotactic radiosurgery.

Object

The purpose of this study was to define the outcomes and risks of stereotactic radiosurgery (SRS) for Spetzler-Martin (SM) Grade III arteriovenous malformations (AVMs).

Methods

Between 1987 and 2009, SRS was performed in 474 patients with SM Grade III AVMs. The AVMs were categorized by scoring the size (S), drainage (D), and location (L): IIIa was a small AVM (S1D1L1, N = 282); IIIb was a medium/deep AVM (S2D1L0, N = 44); and IIIc was a medium/eloquent AVM (S2D0L1, N = 148). The median target volume was 3.8 ml (range 0.1–26.3 ml) and the margin dose was 20 Gy (range 13–25 Gy). Eighty-one patients (17%) underwent prior embolization, and 58 (12%) underwent prior resection.

Results

At a mean follow-up of 89 months, the total obliteration rates documented by angiography or MRI for all SM Grade III AVMs increased from 48% at 3 years to 69% at 4 years, 72% at 5 years, and 77% at 10 years. The SM Grade IIIa AVMs were more likely to obliterate than other subgroups. The cumulative rate of hemorrhage was 2.3% at 1 year, 4.4% at 2 years, 5.5% at 3 years, 6.4% at 5 years, and 9% at 10 years. The SM Grade IIIb AVMs had a significantly higher cumulative rate of hemorrhage. Symptomatic adverse radiation effects were detected in 6%.

Conclusions

Treatment with SRS was an effective and relatively safe management option for SM Grade III AVMs. Although patients with residual AVMs remained at risk for hemorrhage during the latency interval, the cumulative 10-year 9% hemorrhage risk in this series may represent a significant reduction compared with the expected natural history.

The Spetzler-Martin (SM) grading system is a simple, widely accepted, practical tool for assessing the outcomes associated with microsurgical management of brain arteriovenous malformations (AVMs). At experienced vascular centers, the grading system has demonstrated that microsurgery is an effective and relatively safe option for patients with SM Grade I or II AVMs.3,4,6,7,10,11,13,16 In contrast, Grade IV and V AVMs are associated with higher risks and less success regardless of the option selected.13 The SM Grade III AVMs are a heterogeneous group that includes different subtypes of AVMs according to their size, location in critical brain regions, and venous drainage. Nonetheless, relatively few surgical series use a subclassification system to report outcomes of treatment.4,12,21 Pandey et al.17 were among the first to report the multimodality management of SM Grade III AVMs based on subgroup analysis.

Stereotactic radiosurgery (SRS) has been widely used to manage SM Grade III AVMs. The goal of SRS is complete obliteration of the AVM nidus while avoiding postprocedure adverse radiation effects (AREs). Total obliteration appears to reduce the cumulative residual lifetime risk of hemorrhage, even though patients remain at risk for hemorrhage during the latency interval between SRS and obliteration.15 In this report we describe the outcomes of patients who underwent SRS for such AVMs, and we use subgroup analysis to evaluate total obliteration, risk of hemorrhage, and complications of Grade III AVM radiosurgery.

Methods

Patient Population

Between 1987 and 2009, single-stage SRS was performed using the Leksell Gamma Knife (Elekta AB) in 474 patients with SM Grade III AVMs. Eighty-one patients (17%) underwent prior embolization and 58 (12%) underwent prior resection. The AVMs were categorized as follows: Grade IIIa denoted a small AVM (size < 3 cm, presence of deep venous drainage, critical location); Grade IIIb was a medium/deep AVM (size 3–6 cm, presence of deep venous drainage, noncritical location); Grade IIIc was a medium/eloquent AVM (size 3–6 cm, absence of deep venous drainage, critical location); and Grade IIId was a large AVM (size > 6 cm, absence of deep venous drainage, noncritical location). Of the 474 patients with SM Grade III AVMs, 282 (59%) had Grade IIIa, 44 (9%) had Grade IIIb, and 148 (31%) had Grade IIIc. No Grade IIId AVMs were treated in this study. A history of prior hemorrhage before SRS was seen in 74% of Grade IIIa AVMs, in 32% of Grade IIIb AVMs, and in 30% of Grade IIIc AVMs. The patient demographics and AVM characteristics are summarized in Table 1.

TABLE 1:

Demographic data and AVM characteristics in 474 patients whose lesions were treated with SRS*

CharacteristicSM Grade
IIIa, S1D1L1IIIb, S2D1L0IIIc, S2D0L1
total no.28244148
median age in yrs (range)33 (3–79)37 (7–65)35 (5–76)
sex
 M/F152:13023:2177:71
location
 frontal211042
 temporal25722
 parietal15641
 occipital18934
 corpus callosum1130
 basal ganglia4630
 thalamus6310
 cerebellum2149
 brainstem5510
 intraventricular300
 pineal region400
prior hemorrhages pre-SRS210 (74%)14 (32%)44 (30%)
prior resection alone36 (13%)4 (9%)4 (3%)
prior embolization alone28 (10%)8 (18%)31 (21%)
prior embolization + surgery10 (4%)2 (5%)2 (1%)
presence of coexisting aneurysm15 (5%)3 (7%)14 (9%)
median diameter of nidus in mm (range)19 (6–29)32 (30–47)30 (30–45)
median target vol in ml (range)2.2 (0.1–16)7.7 (3.6–21)6.6 (1.2–26)
median margin dose in Gy (range)20 (13–25)17 (14–22)18 (13–25)

Values are number of patients (%) unless stated otherwise. S, D, L = size, drainage, location.

Grade IIIa = small; IIIb = medium/deep; IIIc = medium/eloquent.

Radiosurgery Technique

Our radiosurgical technique has been described in detail in previous reports.10 The margin SRS dose was crafted to include the entire AVM nidus volume, defined as the shunt between the afferent arteries and draining veins. Successfully embolized volumes were not included in the SRS target volume. The SRS was performed with either a model U, B, C, or 4-C Leksell Gamma Knife (Elekta AB). The median diameter of the AVM nidus was 19 mm (range 6–29 mm) in Grade IIIa, 32 mm (range 30–47 mm) in Grade IIIb, and 30 mm (range 30–45 mm) in Grade IIIc. The median target volume was 2.2 ml in Grade IIIa, 7.7 ml in Grade IIIb, and 6.6 ml in Grade IIIc. The median margin dose was 20 Gy in Grade IIIa, 17 Gy in Grade IIIb, and 18 Gy in Grade IIIc.

Patient Follow-Up

After radiosurgery, patients were instructed to undergo clinical and imaging assessments at 6-, 12-, 24-, and 36-month intervals. At the end of 3 years, if MRI suggested complete obliteration, a follow-up angiogram was requested. Complete AVM obliteration was defined as no detectable residual nidus at the time of follow-up angiography, or no evidence of residual flow voids on contrast-enhanced T1- and T2-weighted MRI. Complete angiographic AVM obliteration was defined as disappearance of the nidus and absence of early venous drainage. At any time when a new neurological symptom or sign developed, the patient underwent CT and/or MRI studies to rule out hemorrhage or AREs. This retrospective study was approved by the University of Pittsburgh Institutional Review Board.

Statistical Analysis

Kaplan-Meier survival analysis was carried out to calculate rates of total obliteration and hemorrhage in each subgroup. Patients were censored when lost to follow-up or at the time of an event such as total obliteration and hemorrhage. Consequently, rates of hemorrhage reflect a single hemorrhage experienced by a patient even if he or she had more than one hemorrhage. Annual hemorrhage rates were calculated based on years of follow-up and total number of hemorrhages. The log-rank test was used to assess differences in survival curves, and Cox regression was used to assess hazard ratios (HRs) in multivariate analysis. A value of p < 0.05 was used for statistical significance.

Case Matching of SM Grade IIIb and IIIc AVMs

Forty-four patients with SM Grade IIIb AVMs were eligible to be case control matches in a comparison with 148 patients with SM Grade IIIc AVMs. Propensity score matching was performed between the SM Grade IIIb case cohort and the SM Grade IIIc control cohort.2,8,9 The propensity score was calculated by fitting a logistic regression model in which the following 7 variables were used: age, number of prior hemorrhages, prior embolization, target volume, presence of coexisting aneurysm, radiosurgery-based AVM score, and follow-up duration. We used a nearest neighbor 1:2 matching algorithm based on the propensity score. After propensity score matching, the Mann-Whitney U-test for continuous data and the Fisher exact test for categorical data were used to compare both groups.

Results

At the time of assessment, 426 patients were alive and 48 had died. Twenty patients died of a brain hemorrhage, 1 patient died of untreated symptoms of AREs, and 27 patients died of causes unrelated to their AVM. The median follow-up after SRS was 89 months (range 2–278 months). All living patients had at least 1 year of imaging and clinical assessment.

Response to Radiosurgery

Obliteration of AVM was documented by MRI in 258 patients and by angiography in 198 patients at intervals that ranged from 3 to 10 years after SRS. The total obliteration rates (based on either angiography or MRI criteria) were 48% at 3 years, 69% at 4 years, 72% at 5 years, and 77% at 10 years. The total obliteration rates based on angiography alone were 39% at 3 years, 57% at 4 years, 59% at 5 years, and 62% at 10 years. Obliteration rates calculated by angiography alone in this experience are biased (artificially lowered) by the exclusion of patients with MRI-defined obliteration who declined to undergo angiography. The exact time of obliteration remains unknown because the timing of documentation by imaging varies. The 5-year total obliteration rates after SRS were 74% in Grade IIIa, 72% in Grade IIIb, and 69% in Grade IIIc (Fig. 1).

Fig. 1.
Fig. 1.

Left: Kaplan-Meier curves for total obliteration on MRI or angiography after radiosurgery for AVMs with SM Grade IIIa (small) versus IIIb (medium/deep) versus IIIc (medium/eloquent). Right: Kaplan-Meier curves for total obliteration on MRI or angiography after radiosurgery for AVMs with SM Grade IIIa versus IIIb plus IIIc. The SM Grade IIIa subgroup was significantly associated with a higher rate of total obliteration.

In univariate analysis, factors associated with a higher rate of total obliteration on MRI included maximum diameter < 3 cm (Grade IIIa vs IIIb and IIIc) (Fig. 1), eloquent location (Grade IIIc vs IIIa and IIIb), Grade IIIa compared with IIIb, Grade IIIa compared with IIIc, smaller target volume, higher margin dose, compact nidus shape, no prior embolization, prior hemorrhage, and lower radiosurgery-based AVM score (Table 2). In multivariate analysis, factors associated with a higher rate of total obliteration on MRI included higher margin dose (p < 0.0001, HR 1.11, 95% CI 1.07–1.15) and no prior embolization (p = 0.001, HR 0.52, 95% CI 0.36–0.77) (Table 3). In patients with prior hemorrhage, the median target volume was 5.9 ml (range 0.17–26.3 ml), the median maximum diameter of the nidus was 2.8 cm (range 0.9–4.7 cm), and the median margin dose was 18.5 Gy (range 13.8–25.2 Gy). In patients without prior hemorrhage, the median target volume was 2.5 ml (range 0.1–18.6 ml), the median maximum diameter of the nidus was 2 cm (range 0.6–4.2 cm), and the median margin dose was 20 Gy (range 13–25 Gy). In patients with prior hemorrhage, this was significantly associated with smaller nidus volume (p < 0.001), smaller maximum diameter (p < 0.001), and higher margin dose (p < 0.001) than in those without prior hemorrhage.

TABLE 2:

Univariate analysis of total obliteration and bleeding after radiosurgery*

FactorTO (angio or MRI)TO (angio)Bleeding After SRS
age (younger)0.9190.819<0.0005
sex0.8690.3120.557
max diameter <3 cm (SM IIIa vs IIIb + IIIc)0.002<0.00050.420
deep venous drainage (SM IIIb vs IIIa + IIIc)0.0560.0220.012
eloquent location (SM IIIc vs IIIa + IIIb)0.0480.0130.511
SM IIIa vs SM IIIb0.0200.0060.021
SM IIIa vs SM IIIc0.0120.0020.899
SM IIIb vs SM IIIc0.2790.2070.028
target vol (smaller)<0.00001<0.000010.442
margin dose (higher)<0.00001<0.000010.050
margin dose ≥18 Gy<0.00001<0.000010.125
nidus shape (compact vs diffuse)0.0470.1060.602
prior embolization (no)<0.00050.0080.595
prior bleeding (yes)0.001<0.00050.760
no. of prior ruptures0.0450.0210.686
coexisting aneurysm0.1050.319<0.00005
presence of varix0.3560.6740.117
location (BG, TH, BS)0.2330.0140.338
radiosurgery-based AVM score0.0010.0010.006

Numbers represent p values. angio = angiography; BG = basal ganglion; BS = brainstem; max = maximum; TH = thalamus; TO = total obliteration.

TABLE 3:

Multivariate analysis of total obliteration and bleeding after radiosurgery*

FactorTO (angio or MRI)TO (angio)Bleeding After SRS
p ValueHR95% CIp ValueHR95% CIp ValueHR95% CI
max diameter <3 cm (SM IIIa vs IIIb + IIIc)0.670NANA0.966NANA0.588NANA
deep venous drainage (SM IIIb vs IIIa + IIIc)0.477NANA0.512NANA0.0162.781.21–6.40
eloquent location (SM IIIc vs IIIa + IIIb)0.999NANA0.129NANA0.588NANA
ageNANANANANANA0.0011.041.02–1.06
target vol0.158NANA0.0240.940.89–0.990.913NANA
margin dose<0.00011.111.07–1.15<0.00011.111.05–1.170.144NANA
prior embolization (no)0.0010.520.36–0.770.95NANANANANA
nidus shape0.142NANA0.320NANANANANA
coexisting aneurysmNANANANANANA0.0013.651.62–8.22
no. of prior ruptures0.407NANA0.804NANA0.382NANA

NA = not applicable.

Hemorrhage Before and After Radiosurgery

Thirty-four patients had 38 AVM hemorrhages after SRS. Two patients had 2 hemorrhages, the second of which was fatal in both patients. One patient had 3 hemorrhages and underwent repeat SRS at another hospital. Eighteen patients died after a single AVM hemorrhage at a median of 20 months (range 4–152 months) after SRS. The mortality rate due to AVM hemorrhage after SRS was 4.2%. In 1385 patient-years of estimated hemorrhage risk (the interval from the date of SRS to the date of total obliteration on angiography or the date of last followup imaging showing a residual AVM), we confirmed 38 hemorrhages, which corresponds to an annual hemorrhage rate of 2.7%.

In the 1st year after SRS (462.2 patient-years with 474 patients) 12 hemorrhages occurred; in the 2nd year (415 patient-years with 466 patients) 8 occurred; in the 3rd year (374.7 patient-years with 393 patients) 4 occurred; in the 4th–5th years (584 patient-years with 347 patients) 5 occurred; and in the 6th–10th years (875.7 patient-years with 252 patients) 5 hemorrhages occurred. The annual hemorrhage rates in patients without obliteration, in the interval of 0–1 year, was 2.6%, at 1–2 years it was 1.9%, at 2–3 years it was 1.1%, at 3–5 years it was 0.9%, and at 5–10 years it was 0.6%. Based on Kaplan-Meier analysis (excluding the second hemorrhage in the patient who had more than 2 ruptures), the cumulative rate of AVM hemorrhage after SRS was 2.3% at 1 year, 4.4% at 2 years, 5.5% at 3 years, 6.4% at 5 years, and 9% at 10 years. Eighteen patients (6.4%) with SM Grade IIIa AVMs, 7 (15.9%) with SM Grade IIIb, and 9 (6.1%) with SM Grade IIIc had hemorrhages after SRS. The cumulative 5-year hemorrhage rates were as follows: Grade IIIa AVMs 4.9%, IIIb 14.9%, and IIIc 7.6%. No patient bled after documentation of AVM obliteration was obtained using either MRI or angiography. The detailed outcomes of univariate and multivariate analyses of hemorrhage rates after SRS are shown in Tables 2 and 3.

In univariate analysis, factors associated with an increased hemorrhage rate after SRS included older age, SM Grade IIIb (vs IIIa, IIIc, and IIIa plus IIIc) (Fig. 2), presence of coexisting aneurysm, and higher radiosurgery-based AVM score. In multivariate analyses, factors associated with an increased hemorrhage rate after SRS included SM Grade IIIb (p = 0.016, HR 2.78, 95% CI 1.21–6.40), older age (p = 0.001, HR 1.04, 95% CI 1.02–1.06), and presence of coexisting aneurysm (p = 0.001, HR 3.65, 95% CI 1.62–8.22).

Fig. 2.
Fig. 2.

A: Kaplan-Meier curves for the hemorrhage rate after radiosurgery for AVMs with coexisting aneurysm (AN[+]) versus without coexisting aneurysm (AN[−]). B: Kaplan-Meier curves for the hemorrhage rate after radiosurgery for AVMs with SM Grade IIIa (small) versus IIIb (medium/deep) versus IIIc (medium/eloquent). C: Kaplan-Meier curves for the hemorrhage rate after radiosurgery for AVMs with SM Grade IIIb (cohort) versus IIIc (control). The SM Grade IIIb AVM subgroup was significantly associated with a higher rate of hemorrhage.

In the definition of SM Grade IIIb and IIIc the maximum diameter is the same (3–6 cm), but IIIb had deep venous drainage and IIIc had a critically located AVM.

Comparison of Outcomes of SM Grade IIIb and IIIc AVMs

We evaluated variables that might affect outcome differences between SM Grade IIIb (N = 44) and SM Grade IIIc AVMs (=1N48). In the definition of SM Grades IIIb and IIIc, the maximum diameter range is the same (3–6 cm). The SM Grade IIIb AVMs had deep venous drainage and IIIc AVMs had a location in an area of critical brain function. The SM Grade IIIb AVMs had larger target volumes (p = 0.031), larger maximum diameters (p < 0.001), lower margin doses (p = 0.001), and higher radiosurgery-based scores (p = 0.020) than those of SM Grade IIIc.

The demographic and clinical information of the SM Grade IIIb AVMs (cohort group: N = 44) was matched to the SM Grade IIIc AVMs (control group: N = 88), as shown in Table 4. The radiosurgery-based AVM score (p = 0.545), target volume (p = 0.374), age (p = 0.225), presence of coexisting aneurysm (p = 0.319), and number of prior hemorrhages (p = 0.896) were no different between SM Grade IIIb and IIIc AVMs. We found no difference in the rate of total obliteration after SRS between SM Grade IIIb and IIIc (p = 0.239) after case matching.

TABLE 4:

Comparison of outcomes in groups of patients with SM Grade IIIb versus IIIc AVMs*

CharacteristicCase Group (SM IIIb)Control Group (SM IIIc)p Value
no. of patients4488
preradiosurgery
 age in yrs (mean ± SD)36 ± 1639 ± 140.225
 target vol in ml (mean ± SD)8.4 ± 3.67.9 ± 4.10.374
 no. w/ prior hemorrhage history (%)14 (32)29 (33)0.896
 no. w/ prior embolization (%)10 (23)18 (20)0.764
 no. w/ presence of coexisting aneurysm (%)3 (7)11 (12.5)0.319
 radiosurgery-based AVM score (mean ± SD)1.62 ± 0.501.59 ± 0.470.545
 follow-up period in mos (mean ± SD)75 ± 5793 ± 630.101
postradiosurgery
 % w/ 5-yr TO rate on MRI or angio72690.239
 % w/ hemorrhage rate after SRS at 1 yr4.51.10.032
 % w/ hemorrhage rate after SRS at 2 yrs8.41.1
 % w/ hemorrhage rate after SRS at 3 yrs14.93.6

Cohorts chosen using propensity score and a nearest neighbor 1:2 matching algorithm.

In the control group of patients with SM Grade IIIb AVMs, postradiosurgery cumulative hemorrhage rates were 4.5% at 1 year, and 15% at 3 and 5 years. For patients with SM Grade IIIc AVMs, postradiosurgery cumulative hemorrhage rates were 1.1% at 1 year, 3.6% at 3 years, and 7.8% at 5 years (Fig. 2). The patients with SM Grade IIIb AVMs had a higher rate of hemorrhage (log-rank test: p = 0.032; Cox proportional hazard test: p = 0.043, HR 3.3, 95% CI 1.04–10.3).

Adverse Radiation Effects

Thirty patients (19 [6.7%] with SM Grade IIIa; 3 [6.8%] with Grade IIIb; and 8 [5.4%] with Grade IIIc) developed symptomatic AREs after SRS at a median of 13 months (range 4–40 months). The subclassifications (SM Grades IIIa, IIIb, and IIIc) were not associated with AREs (p = 0.610). Among these 30 patients who had symptomatic AREs, 13 (2.7% of all patients) developed permanent symptomatic AREs. Five patients developed a visual field defect, 4 developed motor weakness, 3 developed extraocular movement disorders, and 1 died of AREs related to refractory brainstem edema. Ten patients (3.5%) with SM Grade IIIa AVMs, none with SM Grade IIIb AVMs, and 3 (2%) with SM Grade IIIc AVMs developed AREs resulting in permanent neurological deficits. Only 1 patient with an SM Grade IIIc AVM sustained a hemorrhage after SRS and permanent symptomatic AREs thereafter.

Nine patients (1.9%) developed delayed cyst formation at a median of 28 months (range 6–210 months) after SRS. One patient required a craniotomy and cyst fenestration that resulted in clinical resolution of symptoms.

Additional Management

Fifty-nine patients with still patent AVMs underwent a second SRS procedure at a median of 42 months (range 18–263 months) after the first procedure. The prescription dose guidelines remained similar for both the initial and the subsequent SRS procedure. Thirty-four patients (58%) had total obliteration documented by MRI or angiography. Nine patients underwent a surgical procedure at a median of 24 months after SRS (range 2–179 months), either for hemorrhage (N = 8) or to obtain obliteration (N = 1). One patient underwent embolization for a coexisting aneurysm 25 months after SRS.

Discussion

Surgical Series of SM Grade III AVMs

Spetzler and Martin20 reported a 16% rate of major and minor deficits after the resection of 25 Grade III AVMs. Heros et al.7 reported a complication rate of 11.4% after resection of 44 SM Grade III AVMs. Lawton et al.13 reported that 30% of 90 patients with SM Grade III AVMs were neurologically worse or dead after surgery. In the present series, 46 (9.7%) of 474 patients who underwent SRS sustained a hemorrhage or permanent symptomatic AREs after treatment. During the latency interval 20 patients died of hemorrhage. The mortality rate was 4.2% and the morbidity rate was 5.5% in this study.

Radiosurgery Series of SM Grade III AVMs

Although the SM grading system is frequently used to describe results after AVM radiosurgery, additional factors critical to successful radiosurgery in these lesions are not relevant to this microsurgical grading system.18 The major predictors of obliteration and complications following SRS are AVM volume, radiation dose, and AVM location. In contrast, the SM grading system is based on AVM size, deep venous draining, and critical location. Relatively few studies have used the SM grading system for predicting obliteration rates and outcome after SRS.

Subgroup Analysis of SM Grade III AVMs

A number of authors have suggested that the SM grading system should be modified to emphasize the differences within SM Grade III AVMs. De Oliveira et al.4 divided SM Grade III AVMs into 2 subgroups based on AVM size. Their proposed subgroups were IIIA (large), for which they emphasized embolization followed by surgery; and IIIB (small, eloquent location), for which they proposed SRS. Lawton12 suggested that SM Grade III AVMs be divided into 4 subgroups. His proposed subgroups of SM III AVMs were very similar to the subgroups evaluated in the present report. In the earlier series, the risk of permanent neurological morbidity or mortality associated with SM Grade IIIa AVMs was 2.9%, with SM Grade IIIb AVMs it was 7.8%, and with SM Grade IIIc AVMs it was 14.8%. Davidson and Morgan3 reported that the surgical morbidity rate was 9% in 32 patients with SM Grade IIIa, 15% in 52 with SM Grade IIIb, 15% in 79 with SM Grade IIIc, and 17% in 6 patients with SM Grade IIId AVMs. Pandey et al.17 estimated complication risks after combining 3 published series (Lawton,12 Davidson and Morgan,3 and Pandey et al.). In their report the complication rates were 4.8% in SM Grade IIIa, 14.4% in SM Grade IIIb, 15.7% in SM Grade IIIc, and 28.6% in SM Grade IIId AVMs. The combination of depth and critical location can be daunting and may make consideration of SRS as an alternative more appealing.12 In the present series, 28 (9.9%) of 282 patients with SM Grade IIIa AVMs, 7 (15.9%) of 44 with SM Grade IIIb AVMs, and 11 (7.4%) of 148 with SM Grade IIIc AVMs developed either a hemorrhage or a permanent symptomatic ARE after SRS.

Andrade-Souza et al.1 reported a radiation-induced complication rate of 25% for patients with SM Grade IIIa AVMs and 26.7% for patients with SM Grade IIIb and IIIc lesions in their series of LINAC-based SRS. In the present series, 10 (3.5%) of 282 patients with SM Grade IIIa AVMs, 0 (0%) of 44 with SM Grade IIIb AVMs, and 3 (2%) of 148 with SM Grade IIIc AVMs developed permanent symptomatic AREs after SRS.

Outcome Predictors

Lawton and colleagues12,13 reported that age, AVM size, unruptured presentation, and diffuse nidus were significant predictors of outcome, whereas critical location and deep venous drainage were borderline predictors of outcome. Pandey et al.17 also found that an unruptured AVM was associated with a significantly higher incidence of new neurological deficits in their multimodality treatment series. In the present series, prior hemorrhage was associated with a higher rate of total obliteration, perhaps related to the fact that SM Grade IIIa (smaller size) AVMs generally received a higher margin SRS dose. Liscák et al.14 also reported that prior hemorrhage was associated with higher rate of total obliteration. In our multivariate analysis, factors associated with a higher rate of total obliteration included higher margin dose and no prior embolization. Higher hemorrhage rates after SRS were associated with SM Grade IIIb, older age, and presence of a coexisting aneurysm. Age and a coexisting aneurysm were predictors of increased risk of hemorrhage after SRS in previous series.9,18

Prior to the present experience, SM Grade IIIb AVMs had not been reported as predictive of increased risk of hemorrhage after SRS. The SM Grade IIIb AVMs have significantly larger target volumes, larger maximum diameters, receive lower margin doses, and have higher radiosurgery-based AVM scores than SM Grade IIIc AVMs. These variables were considered as potential biases. Therefore, we performed a case-matching study of comparison between SM Grade IIIb and IIIc AVMs to reduce potential bias. Even after a case-matched control, patients with SM Grade IIIb AVMs had a higher rate of hemorrhage (p = 0.043, HR 3.3, 95% CI 1.04–10.3). In this study we could not determine whether the presence of deep venous drainage affected the risk of hemorrhage after SRS.

A Suggested Treatment Algorithm for SM Grade III AVMs

Grade III AVMs represent a heterogeneous group, with each subtype possessing different risks. Lawton12 proposed that Grade IIIa AVMs safely undergo resection at experienced centers, whereas Grade IIIc AVMs may be better managed conservatively. The SM Grade IIIb AVMs require carefully individualized treatment recommendations and planning. De Oliveira et al.5 recommended that patients with SM Grade IIIa AVMs should undergo embolization followed by surgery, whereas those with SM Grade IIIb and IIIc AVMs should undergo SRS. Our results suggest that SM Grade IIIa AVMs can be safely treated by SRS, and that SM Grade IIIb AVMs have a higher risk of hemorrhage after SRS compared with SM Grade IIIc lesions.

Weaknesses of the Present Study

We acknowledge the weaknesses of this retrospective outcome analysis. Although angiography is the gold standard for confirming obliteration, 25% of the patients in this series did not undergo angiography after their follow-up MRI revealed obliteration. Although the absence of follow-up angiography in these patients may lead to selection bias, we agree with Pollock et al.,19 who reported that only 3% of patients with MRI-defined obliteration had a residual nidus demonstrated by angiography. In this study we excluded patients who were lost to follow-up, a technique that might produce bias. Nevertheless, during our 25-year experience with AVMs, increasing experience with dose-volume relationships, conformality and selectivity of treatment planning, and reliance on both angiographic and then MRI data, gradually expanded our knowledge and improved SRS techniques and outcomes.

Conclusions

Treatment with SRS was an effective and relatively safe management option for SM Grade III AVMs. Although patients with residual AVMs remained at risk for hemorrhage during the latency interval after radiosurgery, the cumulative 10-year 9% hemorrhage risk in this series may represent a significant reduction compared with the expected natural history. Forty-six (9.7%) of 474 patients who underwent SRS developed hemorrhage or permanent symptomatic AREs after their treatment. It remains to be seen whether SM Grade IIIb AVMs have an increased the risk of hemorrhage during the latency interval after SRS.

Acknowledgment

We thank Professor Douglas Kondziolka, M.D. (New York University Langone Medical Center), for significant contribution to patient management at University of Pittsburgh.

Disclosure

Dr. Lunsford is a consultant for and stockholder in Elekta AB.

Author contributions to the study and manuscript preparation include the following. Conception and design: Kano. Acquisition of data: Kano, Yang, Flannery, Tonetti. Analysis and interpretation of data: Kano. Drafting the article: Kano, Lunsford. 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: Kano. Statistical analysis: Kano. Study supervision: Kano, Lunsford.

This study was presented at the 81st AANS Annual Scientific Meeting, April 27–May 1, 2013, in New Orleans, Louisiana.

References

  • 1

    Andrade-Souza YMZadeh GRamani MScora DTsao MNSchwartz ML: Testing the radiosurgery-based arteriovenous malformation score and the modified Spetzler-Martin grading system to predict radiosurgical outcome. J Neurosurg 103:6426482005

    • Search Google Scholar
    • Export Citation
  • 2

    Austin PCGrootendorst PAnderson GM: A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a Monte Carlo study. Stat Med 26:7347532007

    • Search Google Scholar
    • Export Citation
  • 3

    Davidson ASMorgan MK: How safe is arteriovenous malformation surgery? A prospective, observational study of surgery as first-line treatment for brain arteriovenous malformations. Neurosurgery 66:4985052010

    • Search Google Scholar
    • Export Citation
  • 4

    de Oliveira ETedeschi HRaso J: Comprehensive management of arteriovenous malformations. Neurol Res 20:6736831998

  • 5

    de Oliveira ETedeschi HRaso J: Multidisciplinary approach to arteriovenous malformations. Neurol Med Chir (Tokyo) 38:Suppl1771851998

    • Search Google Scholar
    • Export Citation
  • 6

    Hartmann AStapf CHofmeister CMohr JPSciacca RRStein BM: Determinants of neurological outcome after surgery for brain arteriovenous malformation. Stroke 31:236123642000

    • Search Google Scholar
    • Export Citation
  • 7

    Heros RCKorosue KDiebold PM: Surgical excision of cerebral arteriovenous malformations: late results. Neurosurgery 26:5705781990

    • Search Google Scholar
    • Export Citation
  • 8

    Kano HKondziolka DFlickinger JCPark KJIyer AYang HC: Stereotactic radiosurgery for arteriovenous malformations after embolization: a case-control study. Clinical article. J Neurosurg 117:2652752012

    • Search Google Scholar
    • Export Citation
  • 9

    Kano HKondziolka DFlickinger JCYang HCPark KJFlannery TJ: Aneurysms increase the risk of rebleeding after stereotactic radiosurgery for hemorrhagic arteriovenous malformations. Stroke 43:258625912012

    • Search Google Scholar
    • Export Citation
  • 10

    Kano HLunsford LDFlickinger JCYang HCFlannery TJAwan NR: Stereotactic radiosurgery for arteriovenous malformations, Part 1: management of Spetzler-Martin Grade I and II arteriovenous malformations. Clinical article. J Neurosurg 116:11202012

    • Search Google Scholar
    • Export Citation
  • 11

    Kiriş TSencer ASahinbaş MSencer SImer MIzgi N: Surgical results in pediatric Spetzler-Martin grades I-III intracranial arteriovenous malformations. Childs Nerv Syst 21:69762005

    • Search Google Scholar
    • Export Citation
  • 12

    Lawton MT: Spetzler-Martin Grade III arteriovenous malformations: surgical results and a modification of the grading scale. Neurosurgery 52:7407492003

    • Search Google Scholar
    • Export Citation
  • 13

    Lawton MTKim HMcCulloch CEMikhak BYoung WL: A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery 66:7027132010

    • Search Google Scholar
    • Export Citation
  • 14

    Liscák RVladyka VSimonová GUrgosík DNovotný J JrJanousková L: Arteriovenous malformations after Leksell gamma knife radiosurgery: rate of obliteration and complications. Neurosurgery 60:100510162007

    • Search Google Scholar
    • Export Citation
  • 15

    Maruyama KShin MTago MKishimoto JMorita AKawahara N: Radiosurgery to reduce the risk of first hemorrhage from brain arteriovenous malformations. Neurosurgery 60:4534592007

    • Search Google Scholar
    • Export Citation
  • 16

    Morgan MKRochford AMTsahtsarlis ALittle NFaulder KC: Surgical risks associated with the management of Grade I and II brain arteriovenous malformations. Neurosurgery 61:1 Suppl4174242007

    • Search Google Scholar
    • Export Citation
  • 17

    Pandey PMarks MPHarraher CDWestbroek EMChang SDDo HM: Multimodality management of Spetzler-Martin Grade III arteriovenous malformations. Clinical article. J Neurosurg 116:127912882012

    • Search Google Scholar
    • Export Citation
  • 18

    Pollock BEFlickinger JC: Modification of the radiosurgery-based arteriovenous malformation grading system. Neurosurgery 63:2392432008

    • Search Google Scholar
    • Export Citation
  • 19

    Pollock BEKondziolka DFlickinger JCPatel AKBissonette DJLunsford LD: Magnetic resonance imaging: an accurate method to evaluate arteriovenous malformations after stereotactic radiosurgery. J Neurosurg 85:104410491996

    • Search Google Scholar
    • Export Citation
  • 20

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

  • 21

    Spetzler RFPonce FA: A 3-tier classification of cerebral arteriovenous malformations. Clinical article. J Neurosurg 114:8428492011

    • Search Google Scholar
    • Export Citation

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Article Information

Address correspondence to: Hideyuki Kano, M.D., Ph.D., Department of Neurological Surgery, University of Pittsburgh, Suite B-400, UPMC Presbyterian, 200 Lothrop St., Pittsburgh, PA 15213. email: kanoh@upmc.edu.

Please include this information when citing this paper: published online January 31, 2014; DOI: 10.3171/2013.12.JNS131600.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Left: Kaplan-Meier curves for total obliteration on MRI or angiography after radiosurgery for AVMs with SM Grade IIIa (small) versus IIIb (medium/deep) versus IIIc (medium/eloquent). Right: Kaplan-Meier curves for total obliteration on MRI or angiography after radiosurgery for AVMs with SM Grade IIIa versus IIIb plus IIIc. The SM Grade IIIa subgroup was significantly associated with a higher rate of total obliteration.

  • View in gallery

    A: Kaplan-Meier curves for the hemorrhage rate after radiosurgery for AVMs with coexisting aneurysm (AN[+]) versus without coexisting aneurysm (AN[−]). B: Kaplan-Meier curves for the hemorrhage rate after radiosurgery for AVMs with SM Grade IIIa (small) versus IIIb (medium/deep) versus IIIc (medium/eloquent). C: Kaplan-Meier curves for the hemorrhage rate after radiosurgery for AVMs with SM Grade IIIb (cohort) versus IIIc (control). The SM Grade IIIb AVM subgroup was significantly associated with a higher rate of hemorrhage.

References

  • 1

    Andrade-Souza YMZadeh GRamani MScora DTsao MNSchwartz ML: Testing the radiosurgery-based arteriovenous malformation score and the modified Spetzler-Martin grading system to predict radiosurgical outcome. J Neurosurg 103:6426482005

    • Search Google Scholar
    • Export Citation
  • 2

    Austin PCGrootendorst PAnderson GM: A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a Monte Carlo study. Stat Med 26:7347532007

    • Search Google Scholar
    • Export Citation
  • 3

    Davidson ASMorgan MK: How safe is arteriovenous malformation surgery? A prospective, observational study of surgery as first-line treatment for brain arteriovenous malformations. Neurosurgery 66:4985052010

    • Search Google Scholar
    • Export Citation
  • 4

    de Oliveira ETedeschi HRaso J: Comprehensive management of arteriovenous malformations. Neurol Res 20:6736831998

  • 5

    de Oliveira ETedeschi HRaso J: Multidisciplinary approach to arteriovenous malformations. Neurol Med Chir (Tokyo) 38:Suppl1771851998

    • Search Google Scholar
    • Export Citation
  • 6

    Hartmann AStapf CHofmeister CMohr JPSciacca RRStein BM: Determinants of neurological outcome after surgery for brain arteriovenous malformation. Stroke 31:236123642000

    • Search Google Scholar
    • Export Citation
  • 7

    Heros RCKorosue KDiebold PM: Surgical excision of cerebral arteriovenous malformations: late results. Neurosurgery 26:5705781990

    • Search Google Scholar
    • Export Citation
  • 8

    Kano HKondziolka DFlickinger JCPark KJIyer AYang HC: Stereotactic radiosurgery for arteriovenous malformations after embolization: a case-control study. Clinical article. J Neurosurg 117:2652752012

    • Search Google Scholar
    • Export Citation
  • 9

    Kano HKondziolka DFlickinger JCYang HCPark KJFlannery TJ: Aneurysms increase the risk of rebleeding after stereotactic radiosurgery for hemorrhagic arteriovenous malformations. Stroke 43:258625912012

    • Search Google Scholar
    • Export Citation
  • 10

    Kano HLunsford LDFlickinger JCYang HCFlannery TJAwan NR: Stereotactic radiosurgery for arteriovenous malformations, Part 1: management of Spetzler-Martin Grade I and II arteriovenous malformations. Clinical article. J Neurosurg 116:11202012

    • Search Google Scholar
    • Export Citation
  • 11

    Kiriş TSencer ASahinbaş MSencer SImer MIzgi N: Surgical results in pediatric Spetzler-Martin grades I-III intracranial arteriovenous malformations. Childs Nerv Syst 21:69762005

    • Search Google Scholar
    • Export Citation
  • 12

    Lawton MT: Spetzler-Martin Grade III arteriovenous malformations: surgical results and a modification of the grading scale. Neurosurgery 52:7407492003

    • Search Google Scholar
    • Export Citation
  • 13

    Lawton MTKim HMcCulloch CEMikhak BYoung WL: A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery 66:7027132010

    • Search Google Scholar
    • Export Citation
  • 14

    Liscák RVladyka VSimonová GUrgosík DNovotný J JrJanousková L: Arteriovenous malformations after Leksell gamma knife radiosurgery: rate of obliteration and complications. Neurosurgery 60:100510162007

    • Search Google Scholar
    • Export Citation
  • 15

    Maruyama KShin MTago MKishimoto JMorita AKawahara N: Radiosurgery to reduce the risk of first hemorrhage from brain arteriovenous malformations. Neurosurgery 60:4534592007

    • Search Google Scholar
    • Export Citation
  • 16

    Morgan MKRochford AMTsahtsarlis ALittle NFaulder KC: Surgical risks associated with the management of Grade I and II brain arteriovenous malformations. Neurosurgery 61:1 Suppl4174242007

    • Search Google Scholar
    • Export Citation
  • 17

    Pandey PMarks MPHarraher CDWestbroek EMChang SDDo HM: Multimodality management of Spetzler-Martin Grade III arteriovenous malformations. Clinical article. J Neurosurg 116:127912882012

    • Search Google Scholar
    • Export Citation
  • 18

    Pollock BEFlickinger JC: Modification of the radiosurgery-based arteriovenous malformation grading system. Neurosurgery 63:2392432008

    • Search Google Scholar
    • Export Citation
  • 19

    Pollock BEKondziolka DFlickinger JCPatel AKBissonette DJLunsford LD: Magnetic resonance imaging: an accurate method to evaluate arteriovenous malformations after stereotactic radiosurgery. J Neurosurg 85:104410491996

    • Search Google Scholar
    • Export Citation
  • 20

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

  • 21

    Spetzler RFPonce FA: A 3-tier classification of cerebral arteriovenous malformations. Clinical article. J Neurosurg 114:8428492011

    • Search Google Scholar
    • Export Citation

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