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Radiosurgery for Cerebellar Arteriovenous Malformations: Does Infratentorial Location Affect Outcome?
Peer-Review Reports
Radiosurgery for Cerebellar Arteriovenous Malformations: Does Infratentorial Location Affect Outcome? Dale Ding, Robert M. Starke, Chun-Po Yen, Jason P. Sheehan
Key words Cerebellum - Gamma knife - Intracranial arteriovenous malformation - Radiosurgery - Stroke - Vascular malformations -
- OBJECTIVE:
The cerebellum is an uncommon location for arteriovenous malformations (AVM) with unique angioarchitecture compared to the cerebrum. We evaluate the outcomes of radiosurgery in a cohort of cerebellar AVMs and assess the effect of infratentorial location by comparing them to a matched cohort of supratentorial AVMs.
- METHODS:
Abbreviations and Acronyms AVM: Arteriovenous malformation DSA: Digital subtraction angiography MRI: Magnetic resonance imaging RAS: Radiosurgery AVM scale RBAS: Radiosurgery-based AVM score RIC: Radiation-induced changes Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA To whom correspondence should be addressed: Jason P. Sheehan, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2014.02.007 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
INTRODUCTION The vast majority of intracranial arteriovenous malformations (AVM) are located in the supratentorial compartment (1). Of the 10% to 15% of AVMs that occupy the posterior fossa, the majority reside in the cerebellum (3, 4, 7). Cerebellar AVMs have a very high rate of hemorrhagic presentation comprising approximately 70% to 90% (4, 7, 23, 28, 38). Ruptured AVMs possess a significantly higher prospective risk of hemorrhage than unruptured ones (10, 24, 33). Because of the relatively restricted nature of the posterior fossa, mass effect and edema from cerebellar AVM rupture are more likely to result in clinical manifestations than equivalently sized supratentorial hematomas. Although brainstem AVMs pose significant hurdles to safe microsurgical resection, cerebellar AVMs are more superficial and therefore more amenable to surgical extirpation. Furthermore, because violation of the cerebellar cortex is generally well
From a prospective AVM radiosurgery database of 1400 patients, we identified 60 cerebellar AVM patients with at least 2 years of radiologic follow-up or obliteration. The median volume and prescription dose were 2.3 mL and 22 Gy, respectively. The median radiologic follow-up was 39 months. The cerebellar AVM patients were matched (3:1) to a cohort of supratentorial, lobar AVM patients based on AVM size and patient age. Univariate and multivariate Cox proportional hazards regression analyses were used to identify factors associated with obliteration and favorable outcome.
- RESULTS:
Cerebellar and supratentorial AVMs were similar in baseline characteristics except for an increased incidence of ruptured lesions in the cerebellar AVM cohort (P < .001). Obliteration was achieved in 72% of cerebellar AVMs. Younger age (P [ .019), no preradiosurgery embolization (P < .001), and decreased volume (P [ .034) were independent predictors of obliteration. The annual risk of postradiosurgery hemorrhage in cerebellar AVMs was 1.3%. The rates of symptomatic and permanent radiation-induced changes were 7% and 3%, respectively. Compared with the matched supratentorial AVM cohort, there was no difference in the rates of obliteration, postradiosurgery hemorrhage, or symptomatic radiationinduced changes.
- CONCLUSIONS:
Radiosurgery is an effective treatment modality for cerebellar AVMs with relatively limited adverse events. Infratentorial location did not affect radiosurgery outcomes.
tolerated, many cerebellar AVMs are referred for surgical management. Despite the immediate elimination of microsurgical risk by complete AVM resection, the morbidity and mortality associated with this treatment modality are not inconsequential (28). Radiosurgery has been well established as a therapeutic alternative to microsurgery for AVMs, but the obliteration and complication rates afforded by radiosurgery for cerebellar AVMs are poorly defined. We present our radiosurgery experience with the management of cerebellar AVMs. Additionally, we examine the effect of infratentorial location on radiosurgical outcomes and radiosurgery-related complications by comparing our cerebellar
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AVM cohort to a matched cohort of supratentorial, lobar AVMs.
METHODS Patient Population We reviewed a prospectively collected, institutional review boardeapproved database of 1400 patients with AVMs who were treated with Gamma Knife radiosurgery at our institution over a 21-year span, from 1989 to 2010, and identified all patients harboring cerebellar AVMs. Patients with <2 years of radiologic follow-up were excluded, except those with neuroimaging evidence of obliteration. This yielded 60 patients with
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cerebellar AVMs for analysis. The majority of patients, 35 (58.3%), were female. The median age was 33.9 years, including 6 pediatric patients under the age of 18 (10.0%). Eight patient underwent microsurgical resection (13.3%), and 15 patients underwent endovascular embolization (25.0%) before radiosurgery. The most common presenting symptoms were hemorrhage in 41 patients (68.3%), headache in 12 patients (20.0%), and cerebellar signs (e.g., ataxia) in 3 patients (5.0%). No patients presented with seizures. The characteristics of the cerebellar AVM patient population are detailed in Table 1. Radiosurgery Parameters and AVM Characteristics The Gamma Knife radiosurgery technique is standard and has been previously described (35). Briefly, a Leksell G Frame (Elekta, Inc., Norcross, Georgia, USA) was affixed to the patient’s head with 4 pins under local and monitored anesthesia for adults and general anesthesia for children. Digital subtraction angiography (DSA) was then performed to define the AVM nidus. After 1991, magnetic resonance imaging (MRI) was also used to increase the accuracy of treatment planning. The Leksell Gamma Unit Model U was used before 2001, the Model C was used from 2001 to
Table 1. Cerebellar Arteriovenous Malformation Patient Characteristics Sex
2006, and the Perfexion was used from 2007 onward (Elekta, Inc.). Before 1994, the Kula software was used for dose planning, after which it was replaced with the Gamma Plan software. The AVM locations within the cerebellum were eloquent (i.e., deep cerebellar nuclei, cerebellar peduncles) in 10 patients (16.7%). The venous drainage pattern was deep in 30 patients (50.0%). The median volume was 2.3 mL (range 0.2 to 6.7 mL), and the median prescription dose was 22 Gy (range 14 to 35 Gy). The median isodose line and number of isocenters were 50% and 2, respectively. The Spetzler-Martin grade was I or II in 50 patients (83.4%), III in 9 patients (15.0%), and IV in 1 patient (1.6%) (31). We determined the Virginia radiosurgery AVM scale (RAS), which was 0 to 1 point in 36 patients (60.0%), 2 points in 19 patients (31.7%), and 3 points in 5 patients (8.3%) (34). We also calculated the modified radiosurgery-based AVM score (RBAS), described by Pollock et al. and subsequently validated by Wegner et al., which was median 0.95 (25, 41). The characteristics of the cerebellar AVMs and the radiosurgery parameters are detailed in Table 2. Repeat Radiosurgery If the AVM remained patent 3 years after Gamma Knife radiosurgery, patients were offered repeat radiosurgery. Four patients with residual nidi were treated with repeat
radiosurgery (6.7%). The median residual AVM volume was 0.7 mL (range 0.3 to 2.0 mL). The median prescription and maximum doses were 20 Gy (range 7 to 25 Gy) and 37 Gy (14 to 50 Gy), respectively. The median isodose line was 50% (range 50% to 60%), and the median number of isocenters was 2.5 (range 1 to 7). Radiologic and Clinical Follow-Up Standard radiologic follow-up was comprised of MRI every 6 months for the first 3 years after radiosurgery and then every year afterward. Additional computed tomography or MRI was performed if the patient presented with neurological decline. Hemorrhage was identified by neuroimaging regardless of clinical correlation. Obliteration was defined as absence of flow voids on MRI or absence of anomalous arteriovenous shunting on DSA. DSA was only performed to confirm AVM obliteration after it was determined by MRI. Radiationinduced changes (RIC) were defined on MRI as postradiosurgery perinidal T2-weighted hyperintensities. RICs were classified as symptomatic if they correlated with headache, seizure, and/or focal neurological deficit. Finally, we defined favorable outcome as the combination of complete AVM obliteration, no postradiosurgery hemorrhage, and no permanent RIC (34). Due to the nature of being a tertiary referral center, radiologic and clinical follow-up consisted of a compilation of patient return visits to
Male
25 (41.7%)
Table 2. AVM Characteristics and Treatment Parameters for the Cerebellar AVM Patients
Female
35 (58.3%)
Eloquent location
Eloquent 10 (16.7%), noneloquent 50 (83.3%)
Venous drainage pattern
Superficial 30 (50.0%), deep 30 (50.0%)
Age (years) Mean
36.2
Maximum diameter
Mean 1.9 cm, median 2.0 cm, range 0.6e3.7 cm
Median
33.9
Volume
Mean 2.5 mL, median 2.3 mL, range 0.2e6.7 mL
Range
5.9e66.9
Maximum dose
Mean 40.1 Gy, median 40 Gy, range 28e50 Gy
6 (10.0%)
Pediatric patients (age <18 years)
Prescription dose
Mean 21.7 Gy, median 22 Gy, range 14e35 Gy
Preradiosurgery hemorrhage
44 (73.3%)
Isodose
Mean 55%, median 50%, range 50%e80%
Preradiosurgery embolization
15 (25.0%)
Number of isocenters
Mean 2.2, median 2, range 1e7
Preradiosurgery microsurgical resection
8 (13.3%)
Spetzler-Martin grade
I: 25 (41.7%), II: 25 (41.7%), III: 9 (15.0%), IV: 1 (1.7%)
Radiosurgery-based AVM score
Mean 0.97, median 0.95, range 0.21e1.80 <1.00: 33 (55.0%), 1.00e1.50: 23 (38.3%), 1.51e2.00: 4 (6.7%), >2.00: 0
Virginia radiosurgery AVM scale
0e1 points: 31 (51.7%), 2 points: 19 (31.7%), 3 points: 9 (15.0%), 4 points: 1 (1.7%)
Presenting symptom Hemorrhage
41 (68.3%)
Headache
12 (20.0%)
Cerebellar signs
2
3 (5.0%)
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AVM, arteriovenous malformations.
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our university hospital or outpatient clinics and correspondence with referring hospitals and patients’ local physicians. Overall radiologic follow-up was mean 66.0 months (5.5 years), median 39.0 months (3.3 years), and range 5.3 to 195.4 months (0.4 to 16.3 years). Overall clinical follow-up was mean 74.4 months (6.2 years), median 52.8 months (4.4 years), and range 6.8 to 195.4 months (0.6 to 16.3 years). Matched Cohort of Supratentorial, Lobar AVMs From the same institutional radiosurgery database, we identified a 3:1 matched cohort of supratentorial, lobar AVMs. We excluded AVMs in the primary motor or somatosensory cortices and, similar to the cerebellar AVM cohort, we excluded patients with <2 years radiologic follow-up, except those with neuroimaging evidence of obliteration before 2 years’ follow-up. This yielded a cohort of 180 supratentorial, lobar AVMs matched with the cerebellar AVM cohort for patient gender age, preradiosurgery microsurgery and embolization, AVM maximum diameter and volume, venous drainage pattern, radiosurgical prescription and maximum doses, isodose line, number of isocenters, Spetzler-Martin grade, RBAS, Virginia RAS, and duration of radiologic and clinical follow-up (31, 34, 41). The cerebellar AVMs were more likely to have preradiosurgery hemorrhage (P < .001), whereas more of the supratentorial AVMs were located in eloquent cortex (P < .001). For the matched supratentorial cohort, the median age was 36.2 years and 106 patients were female (58.9%). The median AVM and radiosurgical characteristics were volume 2.3 mL (range 0.3 to 6.9 mL), median prescription dose 23 Gy (range 15 to 36 Gy), maximum dose 44 Gy (range 25 to 52 Gy), isodose line 50% (range 50% to 90%), and number of isocenters 2 (range 1 to 22). The locations were all lobar, with none in the basal ganglia, thalamus, or corpus callosum. Spetzler-Martin grades were I in 51 patients (28.3%), II in 86 patients (47.8%), III in 41 patients (22.8%), and IV in 2 patients (1.1%), without any grade V patients. The median RBAS was 1.01 (range 0.33 to 1.81). The Virginia RAS was 0 to 1 points in 99 patients (55.0%), 2 points in 71 patients (39.4%), and 3 points in 10 patients (5.6%). Obliteration, postradiosurgery hemorrhage, RIC, and favorable outcome were defined in the same manner as in the
RADIOSURGERY FOR CEREBELLAR ARTERIOVENOUS MALFORMATIONS
cerebellar AVM cohort. The comparisons between the cerebellar AVM cohort and the match cohort of supratentorial, lobar AVMs are detailed in Table 3. Statistical Analysis The data are presented as mean and range for continuous variables, and as frequency for categorical variables. Patients with supratentorial lobar and cerebellar AVMs were matched blinded to outcome, in a 3:1 fashion, respectively, based on AVM size and patient age. Matched analysis was carried out as appropriate. Kaplan-Meier survival analysis was used to calculate time to obliteration and actuarial rates of obliteration and postradiosurgery hemorrhage. Univariate Cox proportional hazards conditional (matched) survival analysis was used to test covariates predictive of obliteration after radiosurgery. Factors predictive in univariate
analysis (P < .20) were entered into a multivariate conditional Cox proportional hazards regression analysis. Univariate conditional (matched) analysis was used to test covariates predictive of favorable outcome. Interaction and confounding was assessed through stratification and relevant expansion covariates. Factors predictive in univariate analysis (P < .20) were entered into a multivariate conditional logistic regression analysis. Values of P .05 were considered statistically significant. Statistical analysis was carried out with Stata 10.0 (College Station, Texas, USA).
RESULTS AVM Obliteration After Radiosurgery Complete AVM obliteration was demonstrated on MRI only in 7 patients (11.7%)
Table 3. Comparison of Cerebellar AVM and Supratentorial, Lobar AVM Cohorts
Factor Gender Patient age (years) Age >65 years Preradiosurgery hemorrhage
Cerebellar AVM Cohort (N [ 60)
Supratentorial, Lobar AVM Cohorty (N [ 180)
P Value
Male 41.7%, female 58.3% Male 41.1%, female 58.9%
.940
Mean 36.2, median 33.9
Mean 37.4, median 36.2
.600
3 (5.0%)
7 (3.9%)
.714 < .001*
44 (73.3%)
82 (45.6%)
8 (13.3%)
23 (12.8%)
.912
15 (25.0%)
43 (23.9%)
.862
Maximum diameter (cm)
Mean 1.9, median 2.0
Mean 2.0, median 2.0
.546
Volume (mL)
Mean 2.5, median 2.3
Mean 2.4, median 2.0
.886
Preradiosurgery microsurgical resection Preradiosurgery embolization
< .001*
Eloquent location
10 (16.7%)
83 (46.1%)
Deep venous drainage
30 (50.0%)
75 (41.7%)
.260
Prescription dose (Gy)
Mean 21.7, median 22
Mean 22.2, median 23
.247
Maximum dose (Gy)
Mean 40.1, median 40
Mean 41.6, median 44
.136
Isodose line (%)
Mean 55, median 50
Mean 55, median 50
.812
Number of isocenters
Mean 2.2, median 2
Mean 2.7, median 2
.135
Spetzler-Martin grade
I: 41.7%, II: 41.7%, III: 15.0%, IV: 1.7%
I: 28.3%, II: 47.8%, III: 22.8%, IV: 1.1%
.187
Radiosurgery-based AVM score
Mean 0.97, median 0.95
Mean 0.99, median 1.01
.693
Virginia radiosurgery AVM scale
0e1: 51.7%, 2: 31.7%, 3: 15.0%, 4: 1.7%
0e1: 52.2%, 2: 31.7%, 3: 13.9%, 4: 2.2%
.724
Radiologic follow-up (months)
Mean 66.0, median 39.0
Mean 67.4, median 51.2
.844
Clinical follow-up (months)
Mean 74.4, median 52.8
Mean 75.1, median 61.3
.921
AVM, arteriovenous malformation. *Statistically significant (P < .05). yPrimary motor and sensory cortex AVMs were excluded.
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and confirmed by DSA in 36 patients (60.0%). The cumulative rate of obliteration was 72%. The actuarial rates of obliteration at 3, 5, and 7 years were 51%, 71%, and 76%, respectively. If all patients with <2 years of radiologic follow-up were excluded, even those with AVM obliteration, the rates of MRI only, DSAconfirmed, and cumulative obliteration were 55.1% (27 of 49 patients), 10.2% (5 of 49 patients), and 65.3% (32 of 49) patients, respectively. In the matched supratentorial AVM cohort, obliteration was determined by MRI only in 35 patients (19.4%) and confirmed by DSA in 103 patients (57.2%), for a cumulative obliteration rate of 77%. Compared with the cerebellar AVM cohort, neither the angiographic (P ¼ .706) nor the cumulative (P ¼ .436) obliteration rates were significantly different. The actuarial rates of obliteration for the lobar supratentorial AVMs were 42%, 66%, and 76% at 3, 5, and 7 years, respectively. The rate of obliteration over time is shown in Figure 1. The factors associated with cerebellar AVM obliteration based on univariate Cox proportional hazards regression analysis were lower age, preradiosurgery hemorrhage, preradiosurgery microsurgical resection, no preradiosurgery embolization, decreased maximum diameter, decreased volume, noneloquent location, increased prescription dose, lower Spetzler-Martin grade, lower RBAS, and lower Virginia RAS.
RADIOSURGERY FOR CEREBELLAR ARTERIOVENOUS MALFORMATIONS
Multivariate Cox analysis identified lower age (P ¼ .019), no preradiosurgery embolization (P < .001), and decreased volume (P ¼ .034) to be independent predictors of AVM obliteration. The results of the univariate and multivariate analyses for predictors of obliteration are detailed in Table 4. Figure 2 shows the obliteration rate over time for cerebellar AVMs with and without preradiosurgical embolization. Hemorrhage After Radiosurgery Three patients each had 1 latency period hemorrhage over a total of 237.2 risk years, yielding an annual postradiosurgery hemorrhage rate of 1.3%. At their most recent clinical follow-ups, all 3 patients with postradiosurgery hemorrhage (5.0%) demonstrated clinical deterioration, compared to their preradiosurgery state, at their most recent clinical follow-up (7, 71, 181 months). Two of those patients also had permanent RIC. In the matched supratentorial AVM cohort, 5 patients had 6 latency period hemorrhages over 754 risk years for an annual postradiosurgery hemorrhage risk of 0.8%. The rates of postradiosurgery hemorrhage were not significant different between the 2 cohorts (P ¼ .695). RICs and Cyst Formation After Radiosurgery RICs were evident in 10 patients (17.9%) at a time interval of mean 11.4 months, median 11.7 months, and range 6.0 to 21.4
Figure 1. Kaplan-Meier plot demonstrating the obliteration rate over time for the cerebellar arteriovenous malformation (AVM) and matched supratentorial, lobar AVM cohorts. The x axis shows the number of cerebellar and supratentorial, lobar AVMs remaining at each time point (0, 2, 5, 10, and 15 years).
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months after radiosurgery. The duration of RIC was mean 14.3 months, median 13.5, and range 6.0 to 24.8 months. Symptomatic RIC was observed in 4 patients (6.7%), of which 2 were permanent (3.3%). All patients with RIC had focal neurological deficits. Using the exclusion criteria of all patient with <2 years radiologic follow-up, including those with AVM obliteration, the rates of cumulative, symptomatic, and permanent RIC were 18.4% (9 of 49 patients), 8.2% (4 of 49 patients), and 4.1% (2 of 49 patients), respectively. The matched supratentorial AVM cohort had 65 patients with RIC (37.6%), including 13 patients with symptomatic RIC (7.2%) and 2 patients with permanent RIC (1.1%). The rate of cumulative RIC was higher in the supratentorial AVM cohort (P ¼ .006), but the rates of symptomatic (P ¼ 1.000) and permanent (P ¼ .261) RIC were not significantly different between the 2 groups. There were no postradiosurgery cysts in the cerebellar AVM cohort, compared to 4 cysts in the supratentorial cohort, although the difference was not significant (P ¼ .574). Clinical Outcomes After Radiosurgery Six patients with cerebellar AVMs had clinical improvement (10.0%), with median follow-up 86.1 months (range 36.3 to 195.4 months). Clinical deterioration was observed in 7 cerebellar AVM patients (11.7%), with a median follow-up of 35.0 months (range 6.8 to 181.1 months). Three patients had symptomatic postradiosurgery hemorrhage (5.0%), although 2 of the same patients also have permanent RIC (3.3%). Two patients had new-onset seizures (3.3%) after radiosurgery, one of whom had transiently symptomatic RIC. Favorable outcome (i.e., AVM obliteration and stable or improved neurological outcome) was observed in 42 patients (70.0%) with cerebellar AVMs. If all patients with <2 years of radiologic follow-up were excluded, the rate of favorable outcome was 63.3% (31 of 49 patients). Factors associated with favorable outcome based on univariate Cox proportional hazards regression analysis were male sex, preradiosurgery hemorrhage, preradiosurgery microsurgical resection, no preradiosurgery embolization, decreased maximum diameter, decreased volume, noneloquent location, increased prescription dose, lower Spetzler-Martin grade, and lower RBAS. Independent predictors of favorable outcome in cerebellar
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Table 4. Factors Predicting Obliteration After Radiosurgery Univariate
Factor
Multivariate
Hazard 95% Confidence Hazard 95% Confidence Ratio Interval P Value Ratio Interval P Value
Female gender
1.009
0.751e1.354
.955
e
e
Decreased age
1.007
0.998e1.017
.170*
1.012
1.002e1.021
Preradiosurgery hemorrhage
1.322
0.983e1.778
.065*
NS
NS
NS
Preradiosurgery microsurgical resection
1.807
1.195e2.733
.005*
NS
NS
NS
No preradiosurgery embolization
3.185
2.079e4.902
< .001*
2.502
1.585e3.953
< .001*
Decreased maximum diameter
1.058
1.036e1.081
< .001*
NS
NS
NS
Decreased volume
1.271
1.149e1.403
< .001*
1.127
1.009e1.259
Noneloquent location
1.227
0.904e1.667
.188*
NS
NS
Deep venous drainage
1.050
0.782e1.411
Increased prescription dose
1.088
1.047e1.131
Fewer isocenters
1.029
0.949e1.115
.495
e
e
e
Lower Spetzler-Martin grade
1.224
0.923e1.348
.037*
NS
NS
NS
Lower radiosurgery-based AVM score
2.387
1.511e3.759
< .001*
NS
NS
NS
Lower Virginia Radiosurgery AVM scale
1.267
1.079e1.490
.004*
NS
NS
NS
.745 < .001*
e .019*
.035* NS
e
e
e
NS
NS
NS
AVM, arteriovenous malformation; NS, not significant (P > .05). *Statistically significant (P < .05).
AVM patients, determined by multivariate Cox analysis, were male sex (P ¼ .046), no preradiosurgery embolization (P < .001), and increased prescription dose (P ¼ .001). Favorable outcome was observed in 131 patients (72.8%) in the matched supratentorial AVM cohort, which was not significantly different from the cerebellar AVM cohort (P ¼ .678). The results of the univariate and multivariate analyses for predictors of favorable outcome are detailed in Table 5. Figure 3 shows the rates of favorable outcome for both cerebellar and supratentorial, lobar AVM cohorts based on Virginia RAS. DISCUSSION The tolerance for mass effect, whether from hematoma after AVM rupture or edema associated with treatment-induced complications, is much lower in the small confines of the posterior fossa compared to the
supratentorial compartment. Therefore, one might expect the complication rate for infratentorial AVMs to be higher than supratentorial ones. Given that infratentorial AVMs are more likely to present with hemorrhage, cerebellar hematomas may result in compression of nearby critical brainstem structures or herniation through the superiorly located tentorial incisura or, more commonly, through the inferiorly located foramen magnum. It has been previously suggested that radiosurgery should be reserved for brainstem AVMs and microsurgical resection should be performed for cerebellar lesions (17). However, radiosurgery outcomes for cerebellar AVMs have not previously been rigorously assessed.
Microsurgical Resection of Cerebellar AVMs Until recently, microsurgical series describing outcomes for infratentorial AVMs
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combined brainstem and cerebellar AVMs, therefore making it difficult to properly define the microsurgical outcomes for cerebellar lesions. Despite their shared anatomical location in the posterior fossa and shared white matter interconnections, the brainstem and cerebellum are structurally and functionally distinct structures, thereby presenting vastly disparate challenges to the cerebrovascular neurosurgeon. Although surgical corridors to intrinsic brainstem lesions are limited by the various surrounding critical structures, most cerebellar lesions are readily accessible by standard neurosurgical approaches (9). AVM microsurgery series, including all posterior fossa lesions, reported successful obliteration rates of 83% to 100%, with morbidity and mortality rates of 13% to 25% and 7% to 15%, respectively (4, 7, 38). Rodriguez-Hernandez et al. described a microsurgical series of 60 cerebellar AVMs, of which 73% were ruptured, 70% were <3 cm in size, 30% were eloquent, 57% had deep venous drainage, and 38% were at least Spetzler-Martin grade III (28). In comparison to 401 cerebral AVMs from the same institution, the cerebellar AVMs were more likely to have deep venous drainage (P ¼ .04), less likely to be eloquent (P < .001), and more likely be ruptured (P < .001). Postoperative neurological condition, measured by modified Rankin scale (mRS), was worse in 23% of patients. The postoperative mRS was at least 3 in 25% of patients, including 6 (dead) in 11%. The surgical mortality was 5%. Compared to the cerebral AVM cohort, the cerebellar AVM cohort had worse preoperative (P < .001) and postoperative (P ¼ .01) mRS scores but similar changes in mRS scores after surgery (P ¼ .76). This was the first study to delineate the negative effect of cerebellar location on microsurgical AVM outcomes, although the major contributor to poorer postoperative outcomes seemed to be worse preoperative neurological status. Endovascular Embolization of Cerebellar AVMs The embolization outcomes for cerebellar AVMs have not been specifically described. In general, endovascular embolization is an effective modality for decreasing the vascular supply of an AVM before surgical resection. In the AVM microsurgical series by Rodriguez-Hernandez et al., 55% of the cerebellar AVMs were embolized before
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Figure 2. Kaplan-Meier plot demonstrating the obliteration rate of cerebellar arteriovenous malformations (AVMs) over time divided into those that did and did not undergo preradiosurgery embolization. The x axis shows the number of nonembolized and embolized cerebellar AVMs remaining at each time point (0, 2, 5, 10, and 15 years).
resection (28). As a curative procedure, embolization is only effective in 10% to 20% of cases (16, 21, 22, 40). In a recent series of 350 AVM patients who underwent embolization with Onyx (ethylene vinyl alcohol copolymer, ev3, Irvine, California, USA), complete obliteration was achieved in 179 patients (51%) (29). However, there was a significant selection bias in the aforementioned study, and embolization of less highly selected AVMs will likely result in much lower rates of complete obliteration. Embolization is also commonly used before radiosurgery, and its effect on radiosurgical outcomes has been well described (2, 12, 19, 26). The role of acute embolization for ruptured AVM is poorly defined, and the efficacy of postradiosurgery embolization is currently unknown (36). Radiosurgical Management of Cerebellar AVMs Because of the relative ease by which some cerebellar AVMs may be microsurgically accessed, many of these lesions are likely referred for surgical resection. Additionally the high rate of hemorrhagic presentation and the threat of repeat rupture may lead many cerebrovascular centers to adopt an aggressive surgical approach to cerebellar AVMs. Therefore, a paucity of radiosurgery outcomes data exists for cerebellar AVMs. Patients presenting with AVM rupture should be managed by standard institutional protocols for intracerebral hemorrhage,
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including rapid surgical decompression of the posterior fossa when necessary (20). If the AVM is not resected during the acute decompression, it may be subsequently treated with radiosurgery. At our institution, we typically wait 6 to 12 weeks after AVM rupture to treat a patient with radiosurgery in order to allow the resolution of blood products that may obscure the borders of the nidus; this has been suggested to increase the radiosensitivity of normal parenchyma (32). The cumulative obliteration rate in our series was 72%, with actuarial obliteration rates of 51% and 71% at 3 and 5 years, respectively. Lower age (P ¼ .019), no preradiosurgery embolization (P < .001), and decreased volume (P ¼ .034) were independent predictors of obliteration. Smaller-volume AVMs are more likely to be compact, thereby increasing the accuracy of radiosurgical targeting. Additionally, the treating physician can be more confident in delivering a higher radiosurgical dose to a small nidus volume without incurring a high risk of radiosurgery-induced complications (8). Despite previous findings that preradiosurgery embolization adversely affects obliteration rates, prior embolization was utilized in 25% of the cerebellar AVMs in our series (2, 6, 13, 26, 30). The goal of preradiosurgical embolization at our institution was volume reduction of large or diffuse lesions that could not be effectively targeted by radiosurgery alone, occlusion of high-flow
arterial feeders, and obliteration of perinidal or intranidal aneurysms and arteriovenous shunts. The mechanisms of embolizationinduced attenuation of radiosurgical efficiency have not been fully defined. Preclinical evidence has not supported the longheld notion that permanent embolic agents cause significant radiation beam scattering or absorption (5). Other potential explanations include AVM angiogenesis induced by partial embolization, desensitization of the nidus to the effects of radiation by embolization, and increased difficulty of effectively targeting an embolized AVM with radiosurgery (18, 37, 39). Favorable outcome was seen in 70% of patients. Male gender (P ¼ .046), no preradiosurgical embolization (P < .001), and increased prescription dose (P ¼ .001) were independent predictors of favorable outcome. Given the high propensity of cerebellar AVMs to present with hemorrhage, radiosurgery seems to provide significant stabilization of the nidus with an annual postradiosurgery hemorrhage rate of 1.3% in our series. This compares favorably to a recent meta-analysis of over 3900 patients that reported an annual hemorrhage risk of 4.5% for ruptured AVMs and 2.2% for unruptured lesions (10). Postradiosurgery RIC was symptomatic in 7% and permanent in 3% of cerebellar AVM patients. The combined rate of permanent morbidity after radiosurgery was 12%, including 3% of patients with new-onset seizures. Although the complication rate associated with radiosurgery is lower in our series than a cerebellar AVM microsurgery series, our study was not designed to compare radiosurgical to microsurgical outcomes, and the patient composition and AVM characteristics of radiosurgical and microsurgical series are often dissimilar (28). Infratentorial Location Does Not Affect AVM Radiosurgery Outcomes The differences between the cerebellar AVMs and the matched supratentorial, lobar AVMs in our study, specifically a higher rate of hemorrhagic presentation (P < .001) in the cerebellar AVM cohort and a higher proportion of eloquent location in the cerebral AVM cohort (P < .001), mirror the disparities observed by Rodriguez-Hernandez et al. (28). However, both the favorable and the unfavorable radiosurgery outcomes in our study were not
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Table 5. Factors Predicting Favorable Outcome After Radiosurgery Univariate
Factor
Multivariate
Hazard 95% Confidence Hazard 95% Confidence Ratio Interval P Value Ratio Interval P Value
Male gender
1.499
0.893e2.695
.177*
1.976
1.013e3.861
Decreased age
1.000
0.981e1.019
.969
e
e
e
Preradiosurgery hemorrhage
2.357
1.319e4.209
.004*
NS
NS
NS
Preradiosurgery microsurgical resection
2.913
0.979e8.670
.055*
NS
NS
NS
No preradiosurgery embolization
5.747
3.030e10.870
< .001*
4.386
2.188e8.772
< .001*
Decreased maximum diameter
1.126
1.074e1.181
< .001*
NS
NS
NS
Decreased volume
1.447
1.211e1.730
< .001*
NS
NS
NS
Noneloquent location
1.828
1.032e3.236
.039*
NS
NS
NS
Superficial venous drainage
1.059
0.601e1.869
Increased prescription dose
1.344
1.189e1.520
More isocenters
1.063
0.936e1.206
.346
e
e
e
Lower Spetzler-Martin grade
1.912
1.299e2.817
.001*
NS
NS
NS
Lower radiosurgery-based AVM score
2.381
1.027e5.525
.043*
NS
NS
NS
Lower Virginia Radiosurgery AVM scale
1.443
1.059e1.965
.020*
NS
NS
NS
.842 < .001*
e
e
1.263
1.106e1.442
.046*
e .001*
AVM, arteriovenous malformations; NS, not significant (P > .05). *Statistically significant (P < .05).
affected by infratentorial location. This is in stark contrast to the microsurgical outcomes, which were significantly worse
Figure 3. Bar graph demonstrating the rate of favorable outcome for cerebellar and supratentorial, lobar arteriovenous malformations (AVMs) based on Virginia RAS (VRAS).
for cerebellar AVMs (P ¼ .01) (28). We did not find a difference in the rates of obliteration (P ¼ .436), postradiosurgery hemorrhage (P ¼ .695), symptomatic RIC (P ¼ 1.000), permanent (P ¼ .261) RIC, or favorable outcome (P ¼ .678) between the cerebellar AVM and the supratentorial AVM cohorts. In fact, the only statistically significant difference we identified between the 2 matched cohorts was in overall RIC (P ¼ .006), with the risk of cumulative RIC higher in supratentorial, lobar AVMs. Study Limitations Our study is limited by its retrospective nature. All treatments were performed at a single institution, which further biases our study according to institutional referral patterns and individual treatment preferences of the institution’s cerebrovascular physicians. Patients who presented with
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significant neurological deterioration secondary to mass effect from a ruptured cerebellar AVM were treated with emergent posterior fossa decompression, in which the AVM may have been resected if hematoma evacuation subsequently led to the nidus. In a similar AVM microsurgery series, 68% of patients presented with an mRS score of 3 to 5 (28). Additionally, although cerebellar and supratentorial AVMs were matched based on size and age, and the overall characteristics were similar between final matched cohorts, these AVMs may be inherently different. Cerebellar AVMs had a significantly higher incidence of pretreatment rupture (P < .001), which, because of the high proportion of hemorrhagic presentation patients and relatively low number of cerebellar AVM patients, could not be matched and may affect radiosurgical parameters and outcomes. We were unable to obtain angiographic confirmation of AVM obliteration in 12% of patients. Pollock et al. demonstrated excellent correlation between MRI and angiography, with MRI having a 100% specificity and 91% negative predictive value (27). Although the use of MRI alone to define AVM obliteration has been used by other institutions, we acknowledge that MRI remains suboptimal to angiography for the evaluating residual nidi (14, 15, 11). By only including those patients with <2 years radiologic follow-up who had AVM obliteration, we biased our results toward improved outcomes. However, not taking into account the latency of radiosurgery’s effect would negatively bias our results. To compensate for the bias generated by our follow-up criteria, we have also reported the rates of obliteration, RIC, and favorable outcome assuming exclusion of all patients with <2 years of radiologic follow-up, even those with AVM obliteration. CONCLUSIONS Cerebellar AVMs represent a unique subset of vascular malformations that have a much higher tendency to present with hemorrhage than supratentorial, lobar AVMs. Radiosurgery is an effective management option for these lesions and is associated with a high chance of obliteration as well as a low rate of postradiosurgery latency period hemorrhage. Despite the anatomic and angioarchitectural differences of
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cerebellar compared to cerebral AVMs, radiosurgery outcomes do not seem to be affected by cerebellar location. This finding contrasts with AVM microsurgical outcomes for which cerebellar location has a negative prognostic effect. REFERENCES 1. Al-Shahi R, Warlow C: A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain 124:1900-1926, 2001. 2. Andrade-Souza YM, Ramani M, Scora D, Tsao MN, terBrugge K, Schwartz ML: Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery 60:443-451 [discussion 451-452], 2007. 3. Arnaout OM, Gross BA, Eddleman CS, Bendok BR, Getch CC, Batjer HH: Posterior fossa arteriovenous malformations. Neurosurg Focus 26:E12, 2009. 4. Batjer H, Samson D: Arteriovenous malformations of the posterior fossa. Clinical presentation, diagnostic evaluation, and surgical treatment. J Neurosurg 64:849-856, 1986. 5. Bing F, Doucet R, Lacroix F, Bahary JP, Darsaut T, Roy D, Guilbert F, Raymond J, Weill A: Liquid embolization material reduces the delivered radiation dose: clinical myth or reality? AJNR Am J Neuroradiol 33:320-322, 2012. 6. Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP: Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg 118:958-966, 2013. 7. Drake CG, Friedman AH, Peerless SJ: Posterior fossa arteriovenous malformations. J Neurosurg 64:1-10, 1986. 8. Flickinger JC, Kondziolka D, Lunsford LD, Kassam A, Phuong LK, Liscak R, Pollock B: Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous Malformation Radiosurgery Study Group. Int J Radiat Oncol Biol Phys 46:1143-1148, 2000. 9. Giliberto G, Lanzino DJ, Diehn FE, Factor D, Flemming KD, Lanzino G: Brainstem cavernous malformations: anatomical, clinical, and surgical considerations. Neurosurg Focus 29:E9, 2010. 10. Gross BA, Du R: Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg 118:437-443, 2013. 11. Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Niranjan A, Novotny J Jr, Lunsford LD: Stereotactic radiosurgery for arteriovenous malformations, part 4: management of basal ganglia and thalamus arteriovenous malformations. J Neurosurg 116:33-43, 2012. 12. Kano H, Kondziolka D, Flickinger JC, Park KJ, Iyer A, Yang HC, Liu X, Monaco EA 3rd, Niranjan A, Lunsford LD: Stereotactic radiosurgery after embolization for arteriovenous malformations. Prog Neurol Surg 27:89-96, 2013.
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13. Kano H, Kondziolka D, Flickinger JC, Park KJ, Iyer A, Yang HC, Liu X, Monaco EA 3rd, Niranjan A, Lunsford LD: Stereotactic radiosurgery for arteriovenous malformations after embolization: a casecontrol study. J Neurosurg 117:265-275, 2012. 14. Kano H, Lunsford LD, Flickinger JC, Yang HC, Flannery TJ, Awan NR, Niranjan A, Novotny J Jr, Kondziolka D: Stereotactic radiosurgery for arteriovenous malformations, part 1: management of Spetzler-Martin grade I and II arteriovenous malformations. J Neurosurg 116:11-20, 2012. 15. Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Niranjan A, Novotny J Jr, Lunsford LD: Stereotactic radiosurgery for arteriovenous malformations, part 5: management of brainstem arteriovenous malformations. J Neurosurg 116:44-53, 2012. 16. Katsaridis V, Papagiannaki C, Aimar E: Curative embolization of cerebral arteriovenous malformations (AVMs) with Onyx in 101 patients. Neuroradiology 50:589-597, 2008. 17. Kelly ME, Guzman R, Sinclair J, Bell-Stephens TE, Bower R, Hamilton S, Marks MP, Do HM, Chang SD, Adler JR, Levy RP, Steinberg GK: Multimodality treatment of posterior fossa arteriovenous malformations. J Neurosurg 108:1152-1161, 2008. 18. Kilic K, Konya D, Kurtkaya O, Sav A, Pamir MN, Kilic T: Inhibition of angiogenesis induced by cerebral arteriovenous malformations using gamma knife irradiation. J Neurosurg 106:463-469, 2007. 19. Miller RA, Jankowitz B: Endovascular embolization in combination with radiosurgery for treatment of arteriovenous malformations. Prog Neurol Surg 27:81-88, 2013. 20. Morgenstern LB, Hemphill JC 3rd, Anderson C, Becker K, Broderick JP, Connolly ES Jr, Greenberg SM, Huang JN, MacDonald RL, Messe SR, Mitchell PH, Selim M, Tamargo RJ: Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 41:2108-2129, 2010. 21. Mounayer C, Hammami N, Piotin M, Spelle L, Benndorf G, Kessler I, Moret J: Nidal embolization of brain arteriovenous malformations using Onyx in 94 patients. AJNR Am J Neuroradiol 28: 518-523, 2007. 22. Panagiotopoulos V, Gizewski E, Asgari S, Regel J, Forsting M, Wanke I: Embolization of intracranial arteriovenous malformations with ethylene-vinyl alcohol copolymer (Onyx). AJNR Am J Neuroradiol 30:99-106, 2009. 23. Perret G, Nishioka H: Report on the cooperative study of intracranial aneurysms and subarachnoid hemorrhage. Section VI. Arteriovenous malformations. An analysis of 545 cases of cranio-cerebral arteriovenous malformations and fistulae reported to the cooperative study. J Neurosurg 25:467-490, 1966. 24. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D: Factors that predict the bleeding risk of cerebral arteriovenous malformations. Stroke 27:1-6, 1996. 25. Pollock BE, Flickinger JC: Modification of the radiosurgery-based arteriovenous malformation
grading system. Neurosurgery 63:239-243 [discussion 243], 2008. 26. Pollock BE, Flickinger JC, Lunsford LD, Maitz A, Kondziolka D: Factors associated with successful arteriovenous malformation radiosurgery. Neurosurgery 42:1239-1244 [discussion 1244-1247], 1998. 27. 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 85:1044-1049, 1996. 28. Rodriguez-Hernandez A, Kim H, Pourmohamad T, Young WL, Lawton MT: Cerebellar arteriovenous malformations: anatomic subtypes, surgical results, and increased predictive accuracy of the supplementary grading system. Neurosurgery 71: 1111-1124, 2012. 29. Saatci I, Geyik S, Yavuz K, Cekirge HS: Endovascular treatment of brain arteriovenous malformations with prolonged intranidal Onyx injection technique: long-term results in 350 consecutive patients with completed endovascular treatment course. J Neurosurg 115:78-88, 2011. 30. Schwyzer L, Yen CP, Evans A, Zavoian S, Steiner L: Long-term results of Gamma Knife surgery for partially embolized arteriovenous malformations. Neurosurgery 71:1139-1148, 2012. 31. Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:476-483, 1986. 32. St George EJ, Perks J, Plowman PN: Stereotactic radiosurgery XIV: the role of the haemosiderin ’ring’ in the development of adverse reactions following radiosurgery for intracranial cavernous malformations: a sustainable hypothesis. Br J Neurosurg 16: 385-391, 2002. 33. Stapf C, Mast H, Sciacca RR, Choi JH, Khaw AV, Connolly ES, Pile-Spellman J, Mohr JP: Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology 66:1350-1355, 2006. 34. 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 119:981-987, 2013. 35. Steiner L, Lindquist C, Adler JR, Torner JC, Alves W, Steiner M: Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg 77:1-8, 1992. 36. Stemer AB, Bank WO, Armonda RA, Liu AH, Herzig DW, Bell RS: Acute embolization of ruptured brain arteriovenous malformations. J Neurointerv Surg 5:196-200, 2013. 37. Sure U, Battenberg E, Dempfle A, Tirakotai W, Bien S, Bertalanffy H: Hypoxia-inducible factor and vascular endothelial growth factor are expressed more frequently in embolized than in nonembolized cerebral arteriovenous malformations. Neurosurgery 55:663-669 [discussion 669-670], 2004. 38. Symon L, Tacconi L, Mendoza N, Nakaji P: Arteriovenous malformations of the posterior fossa: a report on 28 cases and review of the literature. Br J Neurosurg 9:721-732, 1995.
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39. 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):41-50, 2008.
41. Wegner RE, Oysul K, Pollock BE, Sirin S, Kondziolka D, Niranjan A, Lunsford LD, Flickinger JC: A modified radiosurgery-based arteriovenous malformation grading scale and its correlation with outcomes. Int J Radiat Oncol Biol Phys 79:1147-1150, 2011.
40. van Rooij WJ, Sluzewski M, Beute GN: Brain AVM embolization with Onyx. AJNR Am J Neuroradiol 28:172-177 [discussion 178], 2007.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any
commercial or financial relationships that could be construed as a potential conflict of interest. Received 12 September 2013; accepted 6 February 2014 Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2014.02.007 Journal homepage: www.WORLDNEUROSURGERY.org
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Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
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9
Radiosurgery for Cerebellar Arteriovenous Malformations: Does Infratentorial Location Affect Outcome? Dale Ding, Robert M. Starke, Chun-Po Yen, Jason P. Sheehan
Key words Cerebellum - Gamma knife - Intracranial arteriovenous malformation - Radiosurgery - Stroke - Vascular malformations -
- OBJECTIVE:
The cerebellum is an uncommon location for arteriovenous malformations (AVM) with unique angioarchitecture compared to the cerebrum. We evaluate the outcomes of radiosurgery in a cohort of cerebellar AVMs and assess the effect of infratentorial location by comparing them to a matched cohort of supratentorial AVMs.
- METHODS:
Abbreviations and Acronyms AVM: Arteriovenous malformation DSA: Digital subtraction angiography MRI: Magnetic resonance imaging RAS: Radiosurgery AVM scale RBAS: Radiosurgery-based AVM score RIC: Radiation-induced changes Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA To whom correspondence should be addressed: Jason P. Sheehan, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2014.02.007 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
INTRODUCTION The vast majority of intracranial arteriovenous malformations (AVM) are located in the supratentorial compartment (1). Of the 10% to 15% of AVMs that occupy the posterior fossa, the majority reside in the cerebellum (3, 4, 7). Cerebellar AVMs have a very high rate of hemorrhagic presentation comprising approximately 70% to 90% (4, 7, 23, 28, 38). Ruptured AVMs possess a significantly higher prospective risk of hemorrhage than unruptured ones (10, 24, 33). Because of the relatively restricted nature of the posterior fossa, mass effect and edema from cerebellar AVM rupture are more likely to result in clinical manifestations than equivalently sized supratentorial hematomas. Although brainstem AVMs pose significant hurdles to safe microsurgical resection, cerebellar AVMs are more superficial and therefore more amenable to surgical extirpation. Furthermore, because violation of the cerebellar cortex is generally well
From a prospective AVM radiosurgery database of 1400 patients, we identified 60 cerebellar AVM patients with at least 2 years of radiologic follow-up or obliteration. The median volume and prescription dose were 2.3 mL and 22 Gy, respectively. The median radiologic follow-up was 39 months. The cerebellar AVM patients were matched (3:1) to a cohort of supratentorial, lobar AVM patients based on AVM size and patient age. Univariate and multivariate Cox proportional hazards regression analyses were used to identify factors associated with obliteration and favorable outcome.
- RESULTS:
Cerebellar and supratentorial AVMs were similar in baseline characteristics except for an increased incidence of ruptured lesions in the cerebellar AVM cohort (P < .001). Obliteration was achieved in 72% of cerebellar AVMs. Younger age (P [ .019), no preradiosurgery embolization (P < .001), and decreased volume (P [ .034) were independent predictors of obliteration. The annual risk of postradiosurgery hemorrhage in cerebellar AVMs was 1.3%. The rates of symptomatic and permanent radiation-induced changes were 7% and 3%, respectively. Compared with the matched supratentorial AVM cohort, there was no difference in the rates of obliteration, postradiosurgery hemorrhage, or symptomatic radiationinduced changes.
- CONCLUSIONS:
Radiosurgery is an effective treatment modality for cerebellar AVMs with relatively limited adverse events. Infratentorial location did not affect radiosurgery outcomes.
tolerated, many cerebellar AVMs are referred for surgical management. Despite the immediate elimination of microsurgical risk by complete AVM resection, the morbidity and mortality associated with this treatment modality are not inconsequential (28). Radiosurgery has been well established as a therapeutic alternative to microsurgery for AVMs, but the obliteration and complication rates afforded by radiosurgery for cerebellar AVMs are poorly defined. We present our radiosurgery experience with the management of cerebellar AVMs. Additionally, we examine the effect of infratentorial location on radiosurgical outcomes and radiosurgery-related complications by comparing our cerebellar
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AVM cohort to a matched cohort of supratentorial, lobar AVMs.
METHODS Patient Population We reviewed a prospectively collected, institutional review boardeapproved database of 1400 patients with AVMs who were treated with Gamma Knife radiosurgery at our institution over a 21-year span, from 1989 to 2010, and identified all patients harboring cerebellar AVMs. Patients with <2 years of radiologic follow-up were excluded, except those with neuroimaging evidence of obliteration. This yielded 60 patients with
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cerebellar AVMs for analysis. The majority of patients, 35 (58.3%), were female. The median age was 33.9 years, including 6 pediatric patients under the age of 18 (10.0%). Eight patient underwent microsurgical resection (13.3%), and 15 patients underwent endovascular embolization (25.0%) before radiosurgery. The most common presenting symptoms were hemorrhage in 41 patients (68.3%), headache in 12 patients (20.0%), and cerebellar signs (e.g., ataxia) in 3 patients (5.0%). No patients presented with seizures. The characteristics of the cerebellar AVM patient population are detailed in Table 1. Radiosurgery Parameters and AVM Characteristics The Gamma Knife radiosurgery technique is standard and has been previously described (35). Briefly, a Leksell G Frame (Elekta, Inc., Norcross, Georgia, USA) was affixed to the patient’s head with 4 pins under local and monitored anesthesia for adults and general anesthesia for children. Digital subtraction angiography (DSA) was then performed to define the AVM nidus. After 1991, magnetic resonance imaging (MRI) was also used to increase the accuracy of treatment planning. The Leksell Gamma Unit Model U was used before 2001, the Model C was used from 2001 to
Table 1. Cerebellar Arteriovenous Malformation Patient Characteristics Sex
2006, and the Perfexion was used from 2007 onward (Elekta, Inc.). Before 1994, the Kula software was used for dose planning, after which it was replaced with the Gamma Plan software. The AVM locations within the cerebellum were eloquent (i.e., deep cerebellar nuclei, cerebellar peduncles) in 10 patients (16.7%). The venous drainage pattern was deep in 30 patients (50.0%). The median volume was 2.3 mL (range 0.2 to 6.7 mL), and the median prescription dose was 22 Gy (range 14 to 35 Gy). The median isodose line and number of isocenters were 50% and 2, respectively. The Spetzler-Martin grade was I or II in 50 patients (83.4%), III in 9 patients (15.0%), and IV in 1 patient (1.6%) (31). We determined the Virginia radiosurgery AVM scale (RAS), which was 0 to 1 point in 36 patients (60.0%), 2 points in 19 patients (31.7%), and 3 points in 5 patients (8.3%) (34). We also calculated the modified radiosurgery-based AVM score (RBAS), described by Pollock et al. and subsequently validated by Wegner et al., which was median 0.95 (25, 41). The characteristics of the cerebellar AVMs and the radiosurgery parameters are detailed in Table 2. Repeat Radiosurgery If the AVM remained patent 3 years after Gamma Knife radiosurgery, patients were offered repeat radiosurgery. Four patients with residual nidi were treated with repeat
radiosurgery (6.7%). The median residual AVM volume was 0.7 mL (range 0.3 to 2.0 mL). The median prescription and maximum doses were 20 Gy (range 7 to 25 Gy) and 37 Gy (14 to 50 Gy), respectively. The median isodose line was 50% (range 50% to 60%), and the median number of isocenters was 2.5 (range 1 to 7). Radiologic and Clinical Follow-Up Standard radiologic follow-up was comprised of MRI every 6 months for the first 3 years after radiosurgery and then every year afterward. Additional computed tomography or MRI was performed if the patient presented with neurological decline. Hemorrhage was identified by neuroimaging regardless of clinical correlation. Obliteration was defined as absence of flow voids on MRI or absence of anomalous arteriovenous shunting on DSA. DSA was only performed to confirm AVM obliteration after it was determined by MRI. Radiationinduced changes (RIC) were defined on MRI as postradiosurgery perinidal T2-weighted hyperintensities. RICs were classified as symptomatic if they correlated with headache, seizure, and/or focal neurological deficit. Finally, we defined favorable outcome as the combination of complete AVM obliteration, no postradiosurgery hemorrhage, and no permanent RIC (34). Due to the nature of being a tertiary referral center, radiologic and clinical follow-up consisted of a compilation of patient return visits to
Male
25 (41.7%)
Table 2. AVM Characteristics and Treatment Parameters for the Cerebellar AVM Patients
Female
35 (58.3%)
Eloquent location
Eloquent 10 (16.7%), noneloquent 50 (83.3%)
Venous drainage pattern
Superficial 30 (50.0%), deep 30 (50.0%)
Age (years) Mean
36.2
Maximum diameter
Mean 1.9 cm, median 2.0 cm, range 0.6e3.7 cm
Median
33.9
Volume
Mean 2.5 mL, median 2.3 mL, range 0.2e6.7 mL
Range
5.9e66.9
Maximum dose
Mean 40.1 Gy, median 40 Gy, range 28e50 Gy
6 (10.0%)
Pediatric patients (age <18 years)
Prescription dose
Mean 21.7 Gy, median 22 Gy, range 14e35 Gy
Preradiosurgery hemorrhage
44 (73.3%)
Isodose
Mean 55%, median 50%, range 50%e80%
Preradiosurgery embolization
15 (25.0%)
Number of isocenters
Mean 2.2, median 2, range 1e7
Preradiosurgery microsurgical resection
8 (13.3%)
Spetzler-Martin grade
I: 25 (41.7%), II: 25 (41.7%), III: 9 (15.0%), IV: 1 (1.7%)
Radiosurgery-based AVM score
Mean 0.97, median 0.95, range 0.21e1.80 <1.00: 33 (55.0%), 1.00e1.50: 23 (38.3%), 1.51e2.00: 4 (6.7%), >2.00: 0
Virginia radiosurgery AVM scale
0e1 points: 31 (51.7%), 2 points: 19 (31.7%), 3 points: 9 (15.0%), 4 points: 1 (1.7%)
Presenting symptom Hemorrhage
41 (68.3%)
Headache
12 (20.0%)
Cerebellar signs
2
3 (5.0%)
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AVM, arteriovenous malformations.
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our university hospital or outpatient clinics and correspondence with referring hospitals and patients’ local physicians. Overall radiologic follow-up was mean 66.0 months (5.5 years), median 39.0 months (3.3 years), and range 5.3 to 195.4 months (0.4 to 16.3 years). Overall clinical follow-up was mean 74.4 months (6.2 years), median 52.8 months (4.4 years), and range 6.8 to 195.4 months (0.6 to 16.3 years). Matched Cohort of Supratentorial, Lobar AVMs From the same institutional radiosurgery database, we identified a 3:1 matched cohort of supratentorial, lobar AVMs. We excluded AVMs in the primary motor or somatosensory cortices and, similar to the cerebellar AVM cohort, we excluded patients with <2 years radiologic follow-up, except those with neuroimaging evidence of obliteration before 2 years’ follow-up. This yielded a cohort of 180 supratentorial, lobar AVMs matched with the cerebellar AVM cohort for patient gender age, preradiosurgery microsurgery and embolization, AVM maximum diameter and volume, venous drainage pattern, radiosurgical prescription and maximum doses, isodose line, number of isocenters, Spetzler-Martin grade, RBAS, Virginia RAS, and duration of radiologic and clinical follow-up (31, 34, 41). The cerebellar AVMs were more likely to have preradiosurgery hemorrhage (P < .001), whereas more of the supratentorial AVMs were located in eloquent cortex (P < .001). For the matched supratentorial cohort, the median age was 36.2 years and 106 patients were female (58.9%). The median AVM and radiosurgical characteristics were volume 2.3 mL (range 0.3 to 6.9 mL), median prescription dose 23 Gy (range 15 to 36 Gy), maximum dose 44 Gy (range 25 to 52 Gy), isodose line 50% (range 50% to 90%), and number of isocenters 2 (range 1 to 22). The locations were all lobar, with none in the basal ganglia, thalamus, or corpus callosum. Spetzler-Martin grades were I in 51 patients (28.3%), II in 86 patients (47.8%), III in 41 patients (22.8%), and IV in 2 patients (1.1%), without any grade V patients. The median RBAS was 1.01 (range 0.33 to 1.81). The Virginia RAS was 0 to 1 points in 99 patients (55.0%), 2 points in 71 patients (39.4%), and 3 points in 10 patients (5.6%). Obliteration, postradiosurgery hemorrhage, RIC, and favorable outcome were defined in the same manner as in the
RADIOSURGERY FOR CEREBELLAR ARTERIOVENOUS MALFORMATIONS
cerebellar AVM cohort. The comparisons between the cerebellar AVM cohort and the match cohort of supratentorial, lobar AVMs are detailed in Table 3. Statistical Analysis The data are presented as mean and range for continuous variables, and as frequency for categorical variables. Patients with supratentorial lobar and cerebellar AVMs were matched blinded to outcome, in a 3:1 fashion, respectively, based on AVM size and patient age. Matched analysis was carried out as appropriate. Kaplan-Meier survival analysis was used to calculate time to obliteration and actuarial rates of obliteration and postradiosurgery hemorrhage. Univariate Cox proportional hazards conditional (matched) survival analysis was used to test covariates predictive of obliteration after radiosurgery. Factors predictive in univariate
analysis (P < .20) were entered into a multivariate conditional Cox proportional hazards regression analysis. Univariate conditional (matched) analysis was used to test covariates predictive of favorable outcome. Interaction and confounding was assessed through stratification and relevant expansion covariates. Factors predictive in univariate analysis (P < .20) were entered into a multivariate conditional logistic regression analysis. Values of P .05 were considered statistically significant. Statistical analysis was carried out with Stata 10.0 (College Station, Texas, USA).
RESULTS AVM Obliteration After Radiosurgery Complete AVM obliteration was demonstrated on MRI only in 7 patients (11.7%)
Table 3. Comparison of Cerebellar AVM and Supratentorial, Lobar AVM Cohorts
Factor Gender Patient age (years) Age >65 years Preradiosurgery hemorrhage
Cerebellar AVM Cohort (N [ 60)
Supratentorial, Lobar AVM Cohorty (N [ 180)
P Value
Male 41.7%, female 58.3% Male 41.1%, female 58.9%
.940
Mean 36.2, median 33.9
Mean 37.4, median 36.2
.600
3 (5.0%)
7 (3.9%)
.714 < .001*
44 (73.3%)
82 (45.6%)
8 (13.3%)
23 (12.8%)
.912
15 (25.0%)
43 (23.9%)
.862
Maximum diameter (cm)
Mean 1.9, median 2.0
Mean 2.0, median 2.0
.546
Volume (mL)
Mean 2.5, median 2.3
Mean 2.4, median 2.0
.886
Preradiosurgery microsurgical resection Preradiosurgery embolization
< .001*
Eloquent location
10 (16.7%)
83 (46.1%)
Deep venous drainage
30 (50.0%)
75 (41.7%)
.260
Prescription dose (Gy)
Mean 21.7, median 22
Mean 22.2, median 23
.247
Maximum dose (Gy)
Mean 40.1, median 40
Mean 41.6, median 44
.136
Isodose line (%)
Mean 55, median 50
Mean 55, median 50
.812
Number of isocenters
Mean 2.2, median 2
Mean 2.7, median 2
.135
Spetzler-Martin grade
I: 41.7%, II: 41.7%, III: 15.0%, IV: 1.7%
I: 28.3%, II: 47.8%, III: 22.8%, IV: 1.1%
.187
Radiosurgery-based AVM score
Mean 0.97, median 0.95
Mean 0.99, median 1.01
.693
Virginia radiosurgery AVM scale
0e1: 51.7%, 2: 31.7%, 3: 15.0%, 4: 1.7%
0e1: 52.2%, 2: 31.7%, 3: 13.9%, 4: 2.2%
.724
Radiologic follow-up (months)
Mean 66.0, median 39.0
Mean 67.4, median 51.2
.844
Clinical follow-up (months)
Mean 74.4, median 52.8
Mean 75.1, median 61.3
.921
AVM, arteriovenous malformation. *Statistically significant (P < .05). yPrimary motor and sensory cortex AVMs were excluded.
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and confirmed by DSA in 36 patients (60.0%). The cumulative rate of obliteration was 72%. The actuarial rates of obliteration at 3, 5, and 7 years were 51%, 71%, and 76%, respectively. If all patients with <2 years of radiologic follow-up were excluded, even those with AVM obliteration, the rates of MRI only, DSAconfirmed, and cumulative obliteration were 55.1% (27 of 49 patients), 10.2% (5 of 49 patients), and 65.3% (32 of 49) patients, respectively. In the matched supratentorial AVM cohort, obliteration was determined by MRI only in 35 patients (19.4%) and confirmed by DSA in 103 patients (57.2%), for a cumulative obliteration rate of 77%. Compared with the cerebellar AVM cohort, neither the angiographic (P ¼ .706) nor the cumulative (P ¼ .436) obliteration rates were significantly different. The actuarial rates of obliteration for the lobar supratentorial AVMs were 42%, 66%, and 76% at 3, 5, and 7 years, respectively. The rate of obliteration over time is shown in Figure 1. The factors associated with cerebellar AVM obliteration based on univariate Cox proportional hazards regression analysis were lower age, preradiosurgery hemorrhage, preradiosurgery microsurgical resection, no preradiosurgery embolization, decreased maximum diameter, decreased volume, noneloquent location, increased prescription dose, lower Spetzler-Martin grade, lower RBAS, and lower Virginia RAS.
RADIOSURGERY FOR CEREBELLAR ARTERIOVENOUS MALFORMATIONS
Multivariate Cox analysis identified lower age (P ¼ .019), no preradiosurgery embolization (P < .001), and decreased volume (P ¼ .034) to be independent predictors of AVM obliteration. The results of the univariate and multivariate analyses for predictors of obliteration are detailed in Table 4. Figure 2 shows the obliteration rate over time for cerebellar AVMs with and without preradiosurgical embolization. Hemorrhage After Radiosurgery Three patients each had 1 latency period hemorrhage over a total of 237.2 risk years, yielding an annual postradiosurgery hemorrhage rate of 1.3%. At their most recent clinical follow-ups, all 3 patients with postradiosurgery hemorrhage (5.0%) demonstrated clinical deterioration, compared to their preradiosurgery state, at their most recent clinical follow-up (7, 71, 181 months). Two of those patients also had permanent RIC. In the matched supratentorial AVM cohort, 5 patients had 6 latency period hemorrhages over 754 risk years for an annual postradiosurgery hemorrhage risk of 0.8%. The rates of postradiosurgery hemorrhage were not significant different between the 2 cohorts (P ¼ .695). RICs and Cyst Formation After Radiosurgery RICs were evident in 10 patients (17.9%) at a time interval of mean 11.4 months, median 11.7 months, and range 6.0 to 21.4
Figure 1. Kaplan-Meier plot demonstrating the obliteration rate over time for the cerebellar arteriovenous malformation (AVM) and matched supratentorial, lobar AVM cohorts. The x axis shows the number of cerebellar and supratentorial, lobar AVMs remaining at each time point (0, 2, 5, 10, and 15 years).
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months after radiosurgery. The duration of RIC was mean 14.3 months, median 13.5, and range 6.0 to 24.8 months. Symptomatic RIC was observed in 4 patients (6.7%), of which 2 were permanent (3.3%). All patients with RIC had focal neurological deficits. Using the exclusion criteria of all patient with <2 years radiologic follow-up, including those with AVM obliteration, the rates of cumulative, symptomatic, and permanent RIC were 18.4% (9 of 49 patients), 8.2% (4 of 49 patients), and 4.1% (2 of 49 patients), respectively. The matched supratentorial AVM cohort had 65 patients with RIC (37.6%), including 13 patients with symptomatic RIC (7.2%) and 2 patients with permanent RIC (1.1%). The rate of cumulative RIC was higher in the supratentorial AVM cohort (P ¼ .006), but the rates of symptomatic (P ¼ 1.000) and permanent (P ¼ .261) RIC were not significantly different between the 2 groups. There were no postradiosurgery cysts in the cerebellar AVM cohort, compared to 4 cysts in the supratentorial cohort, although the difference was not significant (P ¼ .574). Clinical Outcomes After Radiosurgery Six patients with cerebellar AVMs had clinical improvement (10.0%), with median follow-up 86.1 months (range 36.3 to 195.4 months). Clinical deterioration was observed in 7 cerebellar AVM patients (11.7%), with a median follow-up of 35.0 months (range 6.8 to 181.1 months). Three patients had symptomatic postradiosurgery hemorrhage (5.0%), although 2 of the same patients also have permanent RIC (3.3%). Two patients had new-onset seizures (3.3%) after radiosurgery, one of whom had transiently symptomatic RIC. Favorable outcome (i.e., AVM obliteration and stable or improved neurological outcome) was observed in 42 patients (70.0%) with cerebellar AVMs. If all patients with <2 years of radiologic follow-up were excluded, the rate of favorable outcome was 63.3% (31 of 49 patients). Factors associated with favorable outcome based on univariate Cox proportional hazards regression analysis were male sex, preradiosurgery hemorrhage, preradiosurgery microsurgical resection, no preradiosurgery embolization, decreased maximum diameter, decreased volume, noneloquent location, increased prescription dose, lower Spetzler-Martin grade, and lower RBAS. Independent predictors of favorable outcome in cerebellar
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Table 4. Factors Predicting Obliteration After Radiosurgery Univariate
Factor
Multivariate
Hazard 95% Confidence Hazard 95% Confidence Ratio Interval P Value Ratio Interval P Value
Female gender
1.009
0.751e1.354
.955
e
e
Decreased age
1.007
0.998e1.017
.170*
1.012
1.002e1.021
Preradiosurgery hemorrhage
1.322
0.983e1.778
.065*
NS
NS
NS
Preradiosurgery microsurgical resection
1.807
1.195e2.733
.005*
NS
NS
NS
No preradiosurgery embolization
3.185
2.079e4.902
< .001*
2.502
1.585e3.953
< .001*
Decreased maximum diameter
1.058
1.036e1.081
< .001*
NS
NS
NS
Decreased volume
1.271
1.149e1.403
< .001*
1.127
1.009e1.259
Noneloquent location
1.227
0.904e1.667
.188*
NS
NS
Deep venous drainage
1.050
0.782e1.411
Increased prescription dose
1.088
1.047e1.131
Fewer isocenters
1.029
0.949e1.115
.495
e
e
e
Lower Spetzler-Martin grade
1.224
0.923e1.348
.037*
NS
NS
NS
Lower radiosurgery-based AVM score
2.387
1.511e3.759
< .001*
NS
NS
NS
Lower Virginia Radiosurgery AVM scale
1.267
1.079e1.490
.004*
NS
NS
NS
.745 < .001*
e .019*
.035* NS
e
e
e
NS
NS
NS
AVM, arteriovenous malformation; NS, not significant (P > .05). *Statistically significant (P < .05).
AVM patients, determined by multivariate Cox analysis, were male sex (P ¼ .046), no preradiosurgery embolization (P < .001), and increased prescription dose (P ¼ .001). Favorable outcome was observed in 131 patients (72.8%) in the matched supratentorial AVM cohort, which was not significantly different from the cerebellar AVM cohort (P ¼ .678). The results of the univariate and multivariate analyses for predictors of favorable outcome are detailed in Table 5. Figure 3 shows the rates of favorable outcome for both cerebellar and supratentorial, lobar AVM cohorts based on Virginia RAS. DISCUSSION The tolerance for mass effect, whether from hematoma after AVM rupture or edema associated with treatment-induced complications, is much lower in the small confines of the posterior fossa compared to the
supratentorial compartment. Therefore, one might expect the complication rate for infratentorial AVMs to be higher than supratentorial ones. Given that infratentorial AVMs are more likely to present with hemorrhage, cerebellar hematomas may result in compression of nearby critical brainstem structures or herniation through the superiorly located tentorial incisura or, more commonly, through the inferiorly located foramen magnum. It has been previously suggested that radiosurgery should be reserved for brainstem AVMs and microsurgical resection should be performed for cerebellar lesions (17). However, radiosurgery outcomes for cerebellar AVMs have not previously been rigorously assessed.
Microsurgical Resection of Cerebellar AVMs Until recently, microsurgical series describing outcomes for infratentorial AVMs
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combined brainstem and cerebellar AVMs, therefore making it difficult to properly define the microsurgical outcomes for cerebellar lesions. Despite their shared anatomical location in the posterior fossa and shared white matter interconnections, the brainstem and cerebellum are structurally and functionally distinct structures, thereby presenting vastly disparate challenges to the cerebrovascular neurosurgeon. Although surgical corridors to intrinsic brainstem lesions are limited by the various surrounding critical structures, most cerebellar lesions are readily accessible by standard neurosurgical approaches (9). AVM microsurgery series, including all posterior fossa lesions, reported successful obliteration rates of 83% to 100%, with morbidity and mortality rates of 13% to 25% and 7% to 15%, respectively (4, 7, 38). Rodriguez-Hernandez et al. described a microsurgical series of 60 cerebellar AVMs, of which 73% were ruptured, 70% were <3 cm in size, 30% were eloquent, 57% had deep venous drainage, and 38% were at least Spetzler-Martin grade III (28). In comparison to 401 cerebral AVMs from the same institution, the cerebellar AVMs were more likely to have deep venous drainage (P ¼ .04), less likely to be eloquent (P < .001), and more likely be ruptured (P < .001). Postoperative neurological condition, measured by modified Rankin scale (mRS), was worse in 23% of patients. The postoperative mRS was at least 3 in 25% of patients, including 6 (dead) in 11%. The surgical mortality was 5%. Compared to the cerebral AVM cohort, the cerebellar AVM cohort had worse preoperative (P < .001) and postoperative (P ¼ .01) mRS scores but similar changes in mRS scores after surgery (P ¼ .76). This was the first study to delineate the negative effect of cerebellar location on microsurgical AVM outcomes, although the major contributor to poorer postoperative outcomes seemed to be worse preoperative neurological status. Endovascular Embolization of Cerebellar AVMs The embolization outcomes for cerebellar AVMs have not been specifically described. In general, endovascular embolization is an effective modality for decreasing the vascular supply of an AVM before surgical resection. In the AVM microsurgical series by Rodriguez-Hernandez et al., 55% of the cerebellar AVMs were embolized before
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Figure 2. Kaplan-Meier plot demonstrating the obliteration rate of cerebellar arteriovenous malformations (AVMs) over time divided into those that did and did not undergo preradiosurgery embolization. The x axis shows the number of nonembolized and embolized cerebellar AVMs remaining at each time point (0, 2, 5, 10, and 15 years).
resection (28). As a curative procedure, embolization is only effective in 10% to 20% of cases (16, 21, 22, 40). In a recent series of 350 AVM patients who underwent embolization with Onyx (ethylene vinyl alcohol copolymer, ev3, Irvine, California, USA), complete obliteration was achieved in 179 patients (51%) (29). However, there was a significant selection bias in the aforementioned study, and embolization of less highly selected AVMs will likely result in much lower rates of complete obliteration. Embolization is also commonly used before radiosurgery, and its effect on radiosurgical outcomes has been well described (2, 12, 19, 26). The role of acute embolization for ruptured AVM is poorly defined, and the efficacy of postradiosurgery embolization is currently unknown (36). Radiosurgical Management of Cerebellar AVMs Because of the relative ease by which some cerebellar AVMs may be microsurgically accessed, many of these lesions are likely referred for surgical resection. Additionally the high rate of hemorrhagic presentation and the threat of repeat rupture may lead many cerebrovascular centers to adopt an aggressive surgical approach to cerebellar AVMs. Therefore, a paucity of radiosurgery outcomes data exists for cerebellar AVMs. Patients presenting with AVM rupture should be managed by standard institutional protocols for intracerebral hemorrhage,
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including rapid surgical decompression of the posterior fossa when necessary (20). If the AVM is not resected during the acute decompression, it may be subsequently treated with radiosurgery. At our institution, we typically wait 6 to 12 weeks after AVM rupture to treat a patient with radiosurgery in order to allow the resolution of blood products that may obscure the borders of the nidus; this has been suggested to increase the radiosensitivity of normal parenchyma (32). The cumulative obliteration rate in our series was 72%, with actuarial obliteration rates of 51% and 71% at 3 and 5 years, respectively. Lower age (P ¼ .019), no preradiosurgery embolization (P < .001), and decreased volume (P ¼ .034) were independent predictors of obliteration. Smaller-volume AVMs are more likely to be compact, thereby increasing the accuracy of radiosurgical targeting. Additionally, the treating physician can be more confident in delivering a higher radiosurgical dose to a small nidus volume without incurring a high risk of radiosurgery-induced complications (8). Despite previous findings that preradiosurgery embolization adversely affects obliteration rates, prior embolization was utilized in 25% of the cerebellar AVMs in our series (2, 6, 13, 26, 30). The goal of preradiosurgical embolization at our institution was volume reduction of large or diffuse lesions that could not be effectively targeted by radiosurgery alone, occlusion of high-flow
arterial feeders, and obliteration of perinidal or intranidal aneurysms and arteriovenous shunts. The mechanisms of embolizationinduced attenuation of radiosurgical efficiency have not been fully defined. Preclinical evidence has not supported the longheld notion that permanent embolic agents cause significant radiation beam scattering or absorption (5). Other potential explanations include AVM angiogenesis induced by partial embolization, desensitization of the nidus to the effects of radiation by embolization, and increased difficulty of effectively targeting an embolized AVM with radiosurgery (18, 37, 39). Favorable outcome was seen in 70% of patients. Male gender (P ¼ .046), no preradiosurgical embolization (P < .001), and increased prescription dose (P ¼ .001) were independent predictors of favorable outcome. Given the high propensity of cerebellar AVMs to present with hemorrhage, radiosurgery seems to provide significant stabilization of the nidus with an annual postradiosurgery hemorrhage rate of 1.3% in our series. This compares favorably to a recent meta-analysis of over 3900 patients that reported an annual hemorrhage risk of 4.5% for ruptured AVMs and 2.2% for unruptured lesions (10). Postradiosurgery RIC was symptomatic in 7% and permanent in 3% of cerebellar AVM patients. The combined rate of permanent morbidity after radiosurgery was 12%, including 3% of patients with new-onset seizures. Although the complication rate associated with radiosurgery is lower in our series than a cerebellar AVM microsurgery series, our study was not designed to compare radiosurgical to microsurgical outcomes, and the patient composition and AVM characteristics of radiosurgical and microsurgical series are often dissimilar (28). Infratentorial Location Does Not Affect AVM Radiosurgery Outcomes The differences between the cerebellar AVMs and the matched supratentorial, lobar AVMs in our study, specifically a higher rate of hemorrhagic presentation (P < .001) in the cerebellar AVM cohort and a higher proportion of eloquent location in the cerebral AVM cohort (P < .001), mirror the disparities observed by Rodriguez-Hernandez et al. (28). However, both the favorable and the unfavorable radiosurgery outcomes in our study were not
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Table 5. Factors Predicting Favorable Outcome After Radiosurgery Univariate
Factor
Multivariate
Hazard 95% Confidence Hazard 95% Confidence Ratio Interval P Value Ratio Interval P Value
Male gender
1.499
0.893e2.695
.177*
1.976
1.013e3.861
Decreased age
1.000
0.981e1.019
.969
e
e
e
Preradiosurgery hemorrhage
2.357
1.319e4.209
.004*
NS
NS
NS
Preradiosurgery microsurgical resection
2.913
0.979e8.670
.055*
NS
NS
NS
No preradiosurgery embolization
5.747
3.030e10.870
< .001*
4.386
2.188e8.772
< .001*
Decreased maximum diameter
1.126
1.074e1.181
< .001*
NS
NS
NS
Decreased volume
1.447
1.211e1.730
< .001*
NS
NS
NS
Noneloquent location
1.828
1.032e3.236
.039*
NS
NS
NS
Superficial venous drainage
1.059
0.601e1.869
Increased prescription dose
1.344
1.189e1.520
More isocenters
1.063
0.936e1.206
.346
e
e
e
Lower Spetzler-Martin grade
1.912
1.299e2.817
.001*
NS
NS
NS
Lower radiosurgery-based AVM score
2.381
1.027e5.525
.043*
NS
NS
NS
Lower Virginia Radiosurgery AVM scale
1.443
1.059e1.965
.020*
NS
NS
NS
.842 < .001*
e
e
1.263
1.106e1.442
.046*
e .001*
AVM, arteriovenous malformations; NS, not significant (P > .05). *Statistically significant (P < .05).
affected by infratentorial location. This is in stark contrast to the microsurgical outcomes, which were significantly worse
Figure 3. Bar graph demonstrating the rate of favorable outcome for cerebellar and supratentorial, lobar arteriovenous malformations (AVMs) based on Virginia RAS (VRAS).
for cerebellar AVMs (P ¼ .01) (28). We did not find a difference in the rates of obliteration (P ¼ .436), postradiosurgery hemorrhage (P ¼ .695), symptomatic RIC (P ¼ 1.000), permanent (P ¼ .261) RIC, or favorable outcome (P ¼ .678) between the cerebellar AVM and the supratentorial AVM cohorts. In fact, the only statistically significant difference we identified between the 2 matched cohorts was in overall RIC (P ¼ .006), with the risk of cumulative RIC higher in supratentorial, lobar AVMs. Study Limitations Our study is limited by its retrospective nature. All treatments were performed at a single institution, which further biases our study according to institutional referral patterns and individual treatment preferences of the institution’s cerebrovascular physicians. Patients who presented with
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significant neurological deterioration secondary to mass effect from a ruptured cerebellar AVM were treated with emergent posterior fossa decompression, in which the AVM may have been resected if hematoma evacuation subsequently led to the nidus. In a similar AVM microsurgery series, 68% of patients presented with an mRS score of 3 to 5 (28). Additionally, although cerebellar and supratentorial AVMs were matched based on size and age, and the overall characteristics were similar between final matched cohorts, these AVMs may be inherently different. Cerebellar AVMs had a significantly higher incidence of pretreatment rupture (P < .001), which, because of the high proportion of hemorrhagic presentation patients and relatively low number of cerebellar AVM patients, could not be matched and may affect radiosurgical parameters and outcomes. We were unable to obtain angiographic confirmation of AVM obliteration in 12% of patients. Pollock et al. demonstrated excellent correlation between MRI and angiography, with MRI having a 100% specificity and 91% negative predictive value (27). Although the use of MRI alone to define AVM obliteration has been used by other institutions, we acknowledge that MRI remains suboptimal to angiography for the evaluating residual nidi (14, 15, 11). By only including those patients with <2 years radiologic follow-up who had AVM obliteration, we biased our results toward improved outcomes. However, not taking into account the latency of radiosurgery’s effect would negatively bias our results. To compensate for the bias generated by our follow-up criteria, we have also reported the rates of obliteration, RIC, and favorable outcome assuming exclusion of all patients with <2 years of radiologic follow-up, even those with AVM obliteration. CONCLUSIONS Cerebellar AVMs represent a unique subset of vascular malformations that have a much higher tendency to present with hemorrhage than supratentorial, lobar AVMs. Radiosurgery is an effective management option for these lesions and is associated with a high chance of obliteration as well as a low rate of postradiosurgery latency period hemorrhage. Despite the anatomic and angioarchitectural differences of
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cerebellar compared to cerebral AVMs, radiosurgery outcomes do not seem to be affected by cerebellar location. This finding contrasts with AVM microsurgical outcomes for which cerebellar location has a negative prognostic effect. REFERENCES 1. Al-Shahi R, Warlow C: A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain 124:1900-1926, 2001. 2. Andrade-Souza YM, Ramani M, Scora D, Tsao MN, terBrugge K, Schwartz ML: Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery 60:443-451 [discussion 451-452], 2007. 3. Arnaout OM, Gross BA, Eddleman CS, Bendok BR, Getch CC, Batjer HH: Posterior fossa arteriovenous malformations. Neurosurg Focus 26:E12, 2009. 4. Batjer H, Samson D: Arteriovenous malformations of the posterior fossa. Clinical presentation, diagnostic evaluation, and surgical treatment. J Neurosurg 64:849-856, 1986. 5. Bing F, Doucet R, Lacroix F, Bahary JP, Darsaut T, Roy D, Guilbert F, Raymond J, Weill A: Liquid embolization material reduces the delivered radiation dose: clinical myth or reality? AJNR Am J Neuroradiol 33:320-322, 2012. 6. Ding D, Yen CP, Xu Z, Starke RM, Sheehan JP: Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg 118:958-966, 2013. 7. Drake CG, Friedman AH, Peerless SJ: Posterior fossa arteriovenous malformations. J Neurosurg 64:1-10, 1986. 8. Flickinger JC, Kondziolka D, Lunsford LD, Kassam A, Phuong LK, Liscak R, Pollock B: Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous Malformation Radiosurgery Study Group. Int J Radiat Oncol Biol Phys 46:1143-1148, 2000. 9. Giliberto G, Lanzino DJ, Diehn FE, Factor D, Flemming KD, Lanzino G: Brainstem cavernous malformations: anatomical, clinical, and surgical considerations. Neurosurg Focus 29:E9, 2010. 10. Gross BA, Du R: Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg 118:437-443, 2013. 11. Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Niranjan A, Novotny J Jr, Lunsford LD: Stereotactic radiosurgery for arteriovenous malformations, part 4: management of basal ganglia and thalamus arteriovenous malformations. J Neurosurg 116:33-43, 2012. 12. Kano H, Kondziolka D, Flickinger JC, Park KJ, Iyer A, Yang HC, Liu X, Monaco EA 3rd, Niranjan A, Lunsford LD: Stereotactic radiosurgery after embolization for arteriovenous malformations. Prog Neurol Surg 27:89-96, 2013.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any
commercial or financial relationships that could be construed as a potential conflict of interest. Received 12 September 2013; accepted 6 February 2014 Citation: World Neurosurg. (2014). http://dx.doi.org/10.1016/j.wneu.2014.02.007 Journal homepage: www.WORLDNEUROSURGERY.org
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