Radiosurgery for Cerebral Arteriovenous Malformations in Elderly Patients: Effect of Advanced Age on Outcomes After Intervention

Original Article

Radiosurgery for Cerebral Arteriovenous Malformations in Elderly Patients: Effect of Advanced Age on Outcomes After Intervention Dale Ding, Zhiyuan Xu, Chun-Po Yen, Robert M. Starke, Jason P. Sheehan

OBJECTIVE: Cerebral arteriovenous malformations (AVM) are infrequently diagnosed and treated in elderly patients (age, >60 years). We hypothesize that, in contrast to AVM surgical outcomes, radiosurgery outcomes are not adversely affected by increased age. The goals of this casecontrol study are to analyze the radiosurgery outcomes for elderly patients with AVMs and determine the effect of elderly age on AVM radiosurgery outcomes.

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METHODS: We evaluated a prospective database of patients with AVMs treated with radiosurgery from 1989 to 2013. Elderly patients with AVM (age, ‡60 years) with radiologic follow-up of ‡2 years or nidus obliteration were selected for analysis, and matched, in a 1:1 fashion and blinded to outcome, to adult nonelderly patients with AVM (age, <60 years). Statistical analyses were performed to determine actuarial obliteration rates and evaluate the relationship between elderly age and AVM radiosurgery outcomes.

obliteration, radiation-induced changes, or hemorrhage after radiosurgery. CONCLUSIONS: Advanced age does not appear to confer appreciably worse AVM radiosurgery outcomes, unlike its negative effect on AVM surgical outcomes. Thus, when an AVM warrants treatment, radiosurgery may be the preferred treatment for elderly patients.

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RESULTS: The matching processes yielded 66 patients in each of the elderly and nonelderly AVM cohorts. In the elderly AVM cohort, the actuarial AVM obliteration rates at 3, 5, and 10 years were 37%, 65%, and 77%, respectively; the rates of radiologically evident, symptomatic, and permanent radiation-induced changes were 36%, 11%, and 0%, respectively; the annual hemorrhage risk after radiosurgery was 1.1%, and the AVM-related mortality rate was 1.5%. Elderly age was not significantly associated with AVM

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Key words Age groups - Elderly - Gamma knife - Intracranial arteriovenous malformations - Radiosurgery - Stroke - Vascular malformations -

Abbreviations and Acronyms ARUBA: A Randomized Trial of Unruptured Brain AVMs AVM: Arteriovenous malformation CI: Confidence interval CT: Computed tomography MRI: Magnetic resonance imaging RBAS: Radiosurgery-based AVM score

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INTRODUCTION

M

ost cerebral arteriovenous malformations (AVMs) are diagnosed and treated by the third or fourth decades of life (1, 2, 11). Therefore, diagnosis and treatment of an AVM in elderly patients (age,
60 years) is relatively uncommon, although increases in life expectancy over time may result in more frequent AVM diagnoses in the elderly population. A recent metaanalysis of risk factors for AVM hemorrhage found increasing age to be an independent predictor of hemorrhage risk (29). Given the poorer neurological reserve in elderly patients compared with their younger counterparts, stroke secondary to AVM rupture may be particularly devastating in this vulnerable patient population (23). AVM surgical outcomes have been previously shown to be poorer in elderly patients (9, 28, 30). A similar inverse correlation between favorable outcome and age has been described for AVM radiosurgery (40, 52). However, the negative effect of age on post-treatment outcomes in patients with AVM when treated by radiosurgery has not been consistently observed in prior analyses

RIC: Radiation-induced changes SAIVM: Scottish Audit of Intracranial Vascular Malformations SD: Standard deviation VRAS: Virginia radiosurgery AVM scale 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. (2015). http://dx.doi.org/10.1016/j.wneu.2015.05.012 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2015 Elsevier Inc. All rights reserved.

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(6, 10, 12-14, 16-18, 20, 25-27, 33, 36, 41, 53). Furthermore, a study evaluating the radiosurgery outcomes in elderly patients with AVM has not been performed. Therefore, we hypothesize that, unlike surgical outcomes, increased patient age does not significantly worsen AVM radiosurgery outcomes. In this retrospective casecontrol study, our aims are to 1) analyze the outcomes after the treatment of elderly patients with AVM by radiosurgery, 2) define the predictors of obliteration and radiosurgery-induced complications after radiosurgery for AVMs in elderly patients, and 3) determine the effect of elderly age on AVM radiosurgery outcomes. METHODS Patient Selection We retrospectively evaluated a prospective, institutional review board-approved, database of approximately 1400 patients with AVM who were treated with gamma knife radiosurgery at the University of Virginia from 1989 to 2013. The inclusion criteria for the case (elderly) cohort were 1) patient age 60 years or more, 2) sufficient data regarding baseline patient characteristics, AVM features, and outcomes after radiosurgery, and 3) minimum of 2 years of radiologic follow-up after radiosurgery, except for patients with complete AVM obliteration on angiography or magnetic resonance imaging (MRI), who were included even if the duration of radiologic follow-up was less than 2 years. The inclusion criteria for the control (nonelderly) cohort were the same as those for the case cohort, except only adult (<60 years) patients with AVM, but at least 18 years of age, were selected. Patients treated with volume- or dose-staged radiosurgery were excluded. Data and Variables Baseline data, including 1) patient characteristics, 2) AVM angioarchitectural features, and 3) radiosurgery parameters, were extracted from chart review. Patient variables were gender, age, and presenting symptoms. AVM angioarchitectural features were prior interventions (surgical resection and/or embolization), size (maximum diameter and volume of nidus), prior hemorrhage, location (eloquent vs. noneloquent, superficial vs. deep), venous anatomy (number of draining veins, superficial only vs. deep component), and presence of associated aneurysms. Eloquent locations included sensorimotor, language, and visual cortex, hypothalamus and thalamus, internal capsule, brainstem, cerebellar peduncles, and deep cerebellar nuclei (45). Deep locations included basal ganglia, thalamus, and brainstem (52). Based on these variables, the Spetzler-Martin grade, modified radiosurgerybased AVM score (RBAS), and Virginia radiosurgery AVM scale (VRAS) were determined for each nidus (45, 49, 52). Our gamma knife radiosurgery technique for AVMs has been previously described (50). Before 1991, radiosurgical planning did not routinely include the use of MRI in addition to angiography. After 1991, both MRI and angiography were used to enhance the spatial accuracy of radiosurgical planning. From 1989 until June 1994, dose planning was performed using the Kula software, and from July 1994 onward, dose planning was performed using the Gamma Plan software. The radiosurgery variables were prescription dose, maximum dose, isodose line, and number of isocenters.

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Radiologic and Clinical Follow-up Radiologic follow-up after radiosurgery was comprised of serial MRIs every 6 months for the first 2 years, and then annual MRIs after 2 years of follow-up. Additional neuroimaging, either computed tomography (CT) or MRI, was performed in patients with neurological decline after treatment. All follow-up imaging was reviewed by a neuroradiologist and neurosurgeon at the University of Virginia, regardless of where it was obtained. AVM obliteration was defined, on MRI, by a lack of flow voids or, on angiography, by an absence of anomalous arteriovenous shunting. Angiography was used to confirm obliteration based on MRI or to plan further intervention(s) for a residual nidus. Radiation-induced changes (RIC) were defined on follow-up MRI by perinidal T2-weighted hyperintensities (54). The time interval between radiosurgery and the emergence of RIC and the duration of RIC were noted. Symptomatic RIC was defined as RIC accompanied by new or worsening neurological status. Permanent RIC was defined as symptomatic RIC without resolution of the associated neurological deterioration by the most recent clinical follow-up. Latency period hemorrhage was defined by follow-up CT or MRI as the occurrence of AVM-related hemorrhage after radiosurgery, with or without a change in the patient’s neurological status. Cyst formation after radiosurgery was defined by CT or MRI as the development of a cystic cavity within or adjacent to the region occupied by the original nidus. Clinical follow-up was comprised of a combination of clinic and hospital records from the University of Virginia, correspondence with patients’ local physicians, and notes from other referring institutions. After comparing a patient’s neurological condition at the most recent clinical follow-up encounter to the baseline neurological status at the time of radiosurgery, patients were classified as neurologically improved, unchanged, or deteriorated. In the patients who died, the patient age at death, time interval between radiosurgery and death, and cause of death were noted. Patients with seizures at presentation were classified as follows, after comparing the seizure status at the most recent clinical follow-up to the baseline seizure status: 1) seizure remission was defined as the complete resolution of baseline seizures, 2) seizure improvement was defined as seizure remission or reduced seizure frequency, 3) seizure worsening was defined as an increase in the frequency or intensity of baseline seizures, or 4) unchanged seizure status. Patients without seizures at presentation were classified as having de novo seizures if they developed new seizures after radiosurgery. Matching Process and Statistical Analysis Statistical analyses were performed with the IBM SPSS 20 software (SPSS, Armonk, New York) program. All statistical tests were 2sided. Statistical significance was defined as a P value less than 0.05. Data were presented as frequency for categorical variables and as mean with standard deviation (SD) and median with range for continuous variables. Radiologic and clinical outcomes after radiosurgery were reported as frequencies. Using propensity score matching, the elderly patients with AVMs (case cohort) were matched, in a 1:1 fashion and blinded to outcome, to nonelderly patients with AVMs (control cohort) based on prior surgical resection, prior embolization, prior AVM hemorrhage, nidus volume, eloquent AVM location, number of draining veins, presence

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of deep venous drainage, presence of associated aneurysms, and radiosurgical margin dose. Categorical data were compared between the 2 cohorts with Pearson’s c2 test, and continuous data was compared with Student’s t-test. Kaplan-Meier analysis was performed to determine the actuarial obliteration and hemorrhage rates after radiosurgery over time. The log-rank test was used to compare actuarial obliteration and hemorrhage rates after radiosurgery between different subgroups. The annual hemorrhage risk after radiosurgery was calculated by dividing the cumulative number of hemorrhages by the cumulative number of risk years, which was the sum of the time intervals between radiosurgery and AVM obliteration or most recent radiologic follow-up (for incompletely obliterated AVMs) for each patient. Univariate Cox proportional hazards regression analysis was performed on the overall study population (combined case and matched control cohorts) with age, dichotomized between elderly (>60 years) and nonelderly (<60 years) and the aforementioned patient, AVM, and radiosurgery variables to determine factors significantly associated with obliteration. Univariate logistic regression analysis was performed on the overall study population with the same variables to determine factors significantly associated with RIC and hemorrhage after radiosurgery. Due to the low number of cysts after radiosurgery, analysis for factors associated with their occurrence was not performed. Interaction and confounding were assessed through stratification and relevant expansion covariates. Factors that were statistically significant (P < 0.05) in the univariate analyses were entered into a multivariate analysis to determine independent predictors of obliteration (Cox proportional hazards regression) and RIC (binary logistic regression). RESULTS Comparison of Baseline Data for Elderly and Nonelderly AVM Cohorts The overall study population was comprised of 132 patients with AVM, evenly divided between 66 patients in each of the elderly and nonelderly AVM cohorts. Table 1 details the comparison of the patient, AVM, and radiosurgery variables between the 2 cohorts. As expected, patients in the elderly AVM cohort had significantly older (67.0  5.4 vs. 36.1  11.6 years; P < 0.0001) and had, given the age component in its calculation, significantly higher RBAS (1.70  0.31 vs. 1.11  0.30; P < 0.0001). The number of isocenters were significantly higher for the treatment plans of the elderly AVM cohort (2.9  2.7 vs. 2.2  1.2; P ¼ 0.038). The remainder of the patient characteristics, AVM angioarchitectural features, and radiosurgery parameters were similar between the elderly and nonelderly AVM cohorts. In the elderly AVM cohort, the presenting symptoms were hemorrhage in 33 patients (50.0%), seizure in 13 patients (19.7%), headache in 5 patients (7.6%), focal neurological deficit and incidental diagnosis each in 2 patients (3.0%), and aphasia in 1 patient (1.5%), and the most common nidus locations were occipital in 13 (19.7%), temporal in 11 (16.7%), and cerebellar in 10 patients (15.2%). In the elderly AVM cohort, repeat radiosurgery was performed for 9 incompletely obliterated nidi (13.6%). At the time of repeat radiosurgery, the median nidus diameter and volume were 1.1 cm (range, 0.3e1.7 cm) and 0.5 cm3 (range,

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0.1e2.5 cm3), respectively. The median radiosurgery treatment parameters were as follows: margin dose 21 Gy (range, 10e25 Gy), maximum dose 32 Gy (range, 20e50 Gy), isodose line 50% (range, 50%e90%), and number of isocenters 2 (range, 1e8). The median radiologic and clinical follow-up durations after radiosurgery were 47.4 months (range, 5.3e172.4 months) and 57.4 months (range, 6.4e172.4 months), respectively. AVM Obliteration After Radiosurgery In the elderly AVM cohort, total AVM obliteration was achieved in 44 patients (66.7%), including 16 cases documented only by MRI (24.2%) and 28 cases confirmed by angiography (42.4%). Based on Kaplan-Meier analysis, the actuarial obliteration rate was 37% at 3 years, 65% at 5 years, and 77% at 10 years. The median time to obliteration was 46.4 months (95% confidence interval [CI] 34.7e58.2 months). If only elderly AVM patients with at least 2 years of radiologic follow-up were included, the rates of cumulative, MRI only, and angiographic obliteration were 61.1% (33/54 patients), 22.2% (12/54 patients), and 38.9% (21/54 patients), respectively. In the nonelderly AVM cohort, total AVM obliteration was achieved in 46 patients (69.7%), including 7 cases documented only by MRI (10.6%) and 39 cases confirmed by angiography (59.1%). Based on Kaplan-Meier analysis, the actuarial obliteration rate was 49% at 3 years, 63% at 5 years, and 72% at 10 years. The median time to obliteration was 37.1 months (95% CI 26.8e47.3 months). The rates of angiographic (P ¼ 0.056) and cumulative (P ¼ 0.709) obliteration were similar between the elderly and nonelderly AVM cohorts, and the actuarial obliteration rates were similar between the 2 cohorts (P ¼ 0.687, log-rank test; Figure 1). Table 2 details the univariate and multivariate Cox proportional regression analyses for predictors of obliteration in the overall study population. In the univariate analysis, smaller nidus volume (P ¼ 0.005), fewer draining veins (P ¼ 0.005), and higher margin dose (P < 0.0001) were significantly associated with obliteration. In the multivariate analysis, only higher margin dose (P < 0.0001) was found to be an independent predictor of obliteration. Notably, elderly age (P ¼ 0.687) and prior embolization (P ¼ 0.896) were not significantly associated with obliteration. Nidi in the elderly AVM cohort treated with a radiosurgical margin dose of at least 22 Gy were significantly more likely to undergo obliteration (P ¼ 0.001, log-rank test; Figure 2). For AVMs treated with a margin dose of at least 22 Gy, the actuarial obliteration rate was 49% at 3 years, 83% at 5 years, and 93% at 10 years. For AVMs treated with a margin dose of less than 22 Gy, the obliteration rate was 21% at 3 years, 42% at 5 years, and 54% at 10 years. Radiation-induced Changes In the elderly AVM cohort, there was radiologic evidence of RIC in 24 patients (36.4%). Symptomatic RIC was observed in 7 patients (10.6%), all of whom had only transient symptoms. The mean and median time intervals between radiosurgery and the onset of RIC were 12.2  5.6 and 12.2 months, respectively. The mean and median durations of RIC were 27.0  17.4 and 22.5 months, respectively. If only elderly AVM patients with at least 2 years of radiologic follow-up were included, the rates of cumulative,

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Elderly AVM Cohort (N [ 66)

Nonelderly AVM Cohort (N [ 66)

P Value

Age (mean  SD years)

67.0  5.4

36.1  11.6

< 0.0001*

Male gender

36 (54.5%)

31 (47.0%)

0.384

4 (6.1%)

9 (13.6%)

0.144

Prior embolization

11 (16.7%)

7 (10.6%)

0.310

Prior AVM hemorrhage

37 (56.1%)

41 (62.1%)

0.479

Diameter (mean  SD cm)

2.0  0.7

2.0  0.7

0.859

Factor

Prior surgical resection

Volume (mean  SD mL)

2.7  2.4

2.4  1.8

0.374

Eloquent location

39 (59.1%)

43 (65.2%)

0.473

Deep location

12 (18.2%)

20 (30.3%)

0.104

1.7  1.0

1.6  0.9

0.404

36 (54.5%)

30 (45.5%)

0.296

5 (7.6%)

2 (3.0%)

0.244

2.3  0.8 I: 11 (16.7%), II: 29 (43.9%), III: 21 (31.8%), IV: 5 (7.6%), V: 0

2.2  0.8 I: 14 (21.2%), II: 25 (37.9%), III: 26 (39.4%), IV: 1 (1.5%), V: 0

0.524

RBAS (mean  SD)

1.70  0.31 <1.00: 0, 1.00e1.50: 21 (31.8%), 1.51e2.00: 32 (48.5%), >2.00: 13 (19.7%)

1.11  0.30 <1.00: 25 (37.9%), 1.00e1.50: 34 (51.5%), 1.51e2.00: 7 (10.6%), >2.00: 0

< 0.0001*

VRAS (mean  SD)

1.9  1.1 0e1: 24 (36.4%), 2: 26 (39.4%), 3: 10 (15.2%), 4: 6 (9.1%)

2.0  1.0 0e1: 19 (28.8%), 2: 30 (45.5%), 3: 13 (19.7%), 4: 4 (6.1%)

0.555

y

Associated aneurysms

Spetzler-Martin grade (mean  SD)

Prescription dose (mean  SD Gy)

21.7  3.6

21.4  3.0

0.615

Maximum dose (mean  SD Gy)

38.8  7.6

38.3  8.0

0.740

Isodose line (mean  SD %)

57.5  14.0

57.7  13.7

0.921

No. of isocenters (mean  SD)

2.9  2.7

2.2  1.2

0.038*

Duration of radiologic follow-up (mean  SD months)

57.5  39.9

63.1  48.8

0.470

Duration of clinical follow-up (mean  SD months)

70.6  46.0

71.7  51.4

0.900

AVM, arteriovenous malformation; SD, standard deviation; RBAS, radiosurgery-based AVM score, VRAS, Virginia radiosurgery AVM scale. *Statistically significant (P < 0.05). yAssociated aneurysms ¼ intranidal or perinidal aneurysms.

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No. of draining veins Deep venous drainage

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Table 1. Comparison of Patient Characteristics, AVM Angioarchitectural Features, and Radiosurgery Parameters of the Elderly (age,
60 years) and Nonelderly AVM (age, <60 years) Cohorts

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similar between the elderly and nonelderly AVM cohorts, and the time interval between radiosurgery and RIC onset (P ¼ 0.554) and the duration of RIC (P ¼ 0.327) were similar between the 2 cohorts. Table 3 details the univariate and multivariate logistic regression analyses for predictors of RIC in the overall study population. In the univariate analysis, lack of prior hemorrhage (P ¼ 0.008) and larger nidus volume (P ¼ 0.015) were significantly associated with RIC. In the multivariate analysis, lack of prior hemorrhage (P ¼ 0.012) and higher VRAS (P ¼ 0.008) were found to be independent predictors of RIC. Notably, there were no significant associations between elderly age (P ¼ 0.230), number of draining veins (P ¼ 0.271), margin dose (P ¼ 0.606), and the development of RIC.

Figure 1. Kaplan-Meier plots of obliteration over time for nidi in the elderly and nonelderly arteriovenous malformation (AVM) cohorts. The obliteration rates for the elderly AVM cohort at 3, 5, and 10 years were 37%, 65%, and 77%, respectively. The obliteration rates for the nonelderly AVM cohort at 3, 5, and 10 years were 49%, 63%, and 72%, respectively. The actuarial obliteration rates were not statistically different between the 2 cohorts (P ¼ 0.687, log-rank test). The number of patients remaining at each time point is shown under the x-axis.

symptomatic and permanent RIC were 42.6% (23/54 patients), 13.0% (7/54 patients), and 0 (0/54 patients), respectively. In the nonelderly AVM cohort, there was radiologic evidence of RIC in 17 patients (25.8%), Symptomatic RIC was observed in 4 patients (6.1%), including 1 patient with permanent RIC (1.5%). The mean and median time intervals between radiosurgery and the onset of RIC were 13.9  12.2 and 10.1 months, respectively. The mean durations of RIC were 35.8  27.8 and 28.3 months, respectively. The rates of radiologically evident (P ¼ 0.188), symptomatic (P ¼ 0.345), and permanent (P ¼ 0.316) RIC were

Hemorrhage and Cyst Formation after Radiosurgery In the elderly AVM cohort, there were 3 hemorrhages, comprised of a single hemorrhage in each of 3 patients, during the latency period (cumulative, 285 risk years) after radiosurgery, for an annual hemorrhage risk after radiosurgery of 1.1%. Based on Kaplan-Meier analysis, the actuarial hemorrhage rate after radiosurgery was 3.3% at 3 and 5 years and 10.2% at 10 years. In the nonelderly AVM cohort, there were 6 hemorrhages, comprised of a single hemorrhage in each of 6 patients, during the latency period (cumulative, 294 risk years) after radiosurgery, for an annual hemorrhage risk after radiosurgery of 2.0%. Based on Kaplan-Meier analysis, the actuarial hemorrhage rate after radiosurgery was 3.7% at 3 years, 6.6% at 5 years, and 17.6% at 10 years. The occurrence rate of hemorrhage after radiosurgery was similar between the elderly and nonelderly AVM cohorts (P ¼ 0.300), and the actuarial hemorrhage rates after radiosurgery were similar between the 2 cohorts (P ¼ 0.419, log-rank test; Figure 3). No variables were found to have a P value of less than 0.20 in the univariate logistic regression analysis for factors associated with hemorrhage after radiosurgery. Thus, it was not appropriate to perform a multivariate analysis. Notably, elderly age (P ¼ 0.309)

Table 2. Univariate and Multivariate Cox Proportional Hazards Regression Analyses for Predictors of Obliteration After AVM Radiosurgery Univariate Factor

Multivariate

Hazard Ratio

95% CI

P Value

Hazard Ratio

95% CI

P Value

Prior AVM hemorrhage

1.35

0.873e2.08

0.178

—

—

NS

Smaller volume

1.19

1.05e1.35

0.005*

—

—

NS

Fewer draining veins

1.49

1.12e1.97

0.005*

—

—

NS

No associated aneurysms

1.84

0.850e4.00

0.122

—

—

NS

Lower Spetzler-Martin grade

1.23

0.951e1.60

0.115

—

—

NS

Lower VRAS

1.22

0.969e1.55

0.089

—

—

NS

Higher margin dose

1.18

1.10e1.26

< 0.0001*

1.16

1.07e1.25

< 0.0001*

Only factors with P < 0.20 in the univariate analysis were listed. AVM, arteriovenous malformation; CI, confidence interval; NS, not significant (P > 0.05); VRAS, Virginia radiosurgery AVM scale. *Statistically significant (P < 0.05).

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Figure 2. Kaplan-Meier plots of obliteration over time for nidi in the elderly arteriovenous malformation cohort treated with a margin dose of
22 Gy compared with nidi treated with a margin dose of <22 Gy. For patients in whom the margin dose was
22 Gy, the obliteration rates at 3, 5, and 10 years were 49%, 83%, and 93%, respectively. For patients in whom the margin dose was <22 Gy, the obliteration rates at 3, 5, and 10 years were 21%, 42%, and 54%, respectively. The obliteration rates were significantly higher for nidi treated with a margin dose of
22 Gy (P ¼ 0.001, log-rank test). The number of patients remaining at each time point is shown under the x-axis.

was not significantly associated with hemorrhage after radiosurgery. There were no cases of cyst formation after radiosurgery in the elderly AVM cohort and 1 case in the nonelderly AVM cohort (1.5%). The occurrence rate of cyst formation after radiosurgery was not significantly different between the 2 cohorts (P ¼ 0.316).

Clinical Outcomes in Elderly AVM Patients after Radiosurgery At the most recent clinical follow-up, 12 patients in the elderly AVM cohort had died (18.2%). The median age at death was 75.9 years (range, 67.5e82.5 years), and the median time interval between radiosurgery and death was 100.5 months (range, 18.3e130.6 months). The causes of death were AVM hemorrhage

in 1 patient (age at death, 82.5 years; time interval from radiosurgery to death, 18.3 months), an AVM-unrelated cause in 7 patients (10.6%), and unknown in 4 patients (6.1%). The AVM-related mortality rate was 1.5%, if the unknown causes of death were assumed to be unrelated to the AVM, whereas the AVM-related mortality rate was 7.6%, if the unknown causes of death were assumed to be AVM related. In the 54 surviving patients (overall survival, 81.8%), neurological improvement was observed in 9 patients (16.7%), whereas neurological deterioration occurred in 1 patient (1.9%). The remaining 44 patients were unchanged from their baseline neurological status (81.5%). For patients in the elderly AVM cohort with seizures at presentation, the incidence of seizure improvement after radiosurgery was 61.5% (8/13 patients), including 15.4% seizure remission (2/13 patients) and 46.2% decreased seizure frequency (6/13 patients). Baseline seizure status was unchanged in 38.5% (5/13 patients), and there were no cases of worsening seizures (0/13 patients). For patients in the elderly AVM cohort without seizures at presentation, the incidence de novo seizures after radiosurgery was 1.9% (1/53 patients).

DISCUSSION The management of AVMs should include the consideration of patient, AVM, and treatment factors. The risks of intervention must be weighed against an AVM’s natural history, which has been shown to vary considerably based on the angioarchitecture of the nidus (46). Given the correlation of increasing age with both AVM hemorrhage risk and procedural morbidity, a significant dilemma arises regarding the appropriate management of AVMs in elderly patients (5, 30, 40). In a study of 240 patients with AVM followed for a mean of 10 years, ApSimon et al. (5) reported that the incidence of initial hemorrhage was 40% in the 60 to 69 year age bracket, compared with 4.6% in the 0 to 9 years age bracket (5). Kim et al. (29) performed a meta-analysis of 4 large AVM cohort, comprising more than 2500 patients, and found increasing age to be an independent predictor of hemorrhage (hazard ratio, 1.34 per decade, 95% CI 1.17e1.53). Despite a positive correlation between AVM hemorrhage risk and increasing age, the shorter life expectancy of elderly patients may yield a lower cumulative lifetime risk of AVM hemorrhage than for

Table 3. Univariate and Multivariate Logistic Regression Analyses for Predictors of Radiation-Induced Changes After AVM Radiosurgery Univariate Factor No prior AVM hemorrhage

Multivariate

Odds Ratio

95% CI

P Value

Odds Ratio

95% CI

P Value

2.83

1.31e6.06

0.008*

3.62

1.33e9.90

0.012*

Larger volume

1.26

1.05e1.52

0.015*

—

—

NS

Superficial venous drainage

1.74

0.820e3.69

0.150

—

—

NS

Higher VRAS

1.39

0.943e2.06

0.096

1.87

1.18e2.97

0.008*

Only factors with P < 0.20 in the univariate analysis were listed. AVM, arteriovenous malformation; CI, confidence interval; NS, not significant (P > 0.05); VRAS, Virginia radiosurgery AVM scale. *Statistically significant (P < 0.05).

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Figure 3. Kaplan-Meier plots of hemorrhage after radiosurgery over time for nidi in the elderly and nonelderly arteriovenous malformation (AVM) cohorts. The hemorrhage rates after radiosurgery for the elderly AVM cohort at 3, 5, and 10 years were 3.3%, 3.3%, and 10.2%, respectively. The hemorrhage rates after radiosurgery for the nonelderly AVM cohort at 3, 5, and 10 years were 3.7%, 6.6%, and 17.6%, respectively. The actuarial obliteration rates were similar between the 2 cohorts (P ¼ 0.419, log-rank test). The number of patients remaining at each time point is shown under the x-axis.

younger patients, thereby potentially shifting the balance of treatment morbidity and natural history away from intervention. The Spetzler-Martin grading system only accounted for nidusrelated factors in the stratification of surgical risks in patients with AVM (45). Subsequently, Lawton et al. (30) developed a supplementary grading scale for AVM surgical outcomes, which incorporated age (<20 years ¼ 1 point, 20e40 years ¼ 2 points, >40 years ¼ 3 points), presence or absence of prior AVM hemorrhage (ruptured ¼ 0 points, unruptured ¼ 1 point), and compact or diffuse nidus morphology (compact ¼ 0 points, diffuse ¼ 1 point). The supplementary grading scale was shown to have a greater predictive accuracy (P ¼ 0.042) than the Spetzler-Martin grading system with regard to postoperative neurological outcomes. Recently, the predictive capability of the combination of the supplementary and Spetzler-Martin grading scales was validated in a multicenter study of 1009 surgically treated AVMs (28). Thus, increasing age has been shown to have a detrimental effect on AVM surgical outcomes. The prevalence and severity of medical comorbidities rise with increasing patient age. Because surgical resection places a significantly higher physiologic burden on a patient than radiosurgery, it is reasonable to assume that the negative effect of systemic disease on treatment outcomes is relatively higher for surgery than radiosurgery. The key findings of this study are that elderly age (
60 years) was not significantly associated with AVM obliteration after radiosurgery (P ¼ 0.687), RIC (P ¼ 0.230), or hemorrhage after radiosurgery (P ¼ 0.309). Radiosurgery avoids the upfront morbidity of surgical resection, which can be substantial and particularly devastating in elderly patients. The minimally invasive nature of radiosurgery, minimal hospital stay, and avoidance of general anesthesia may allow patients with AVM who are treated

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with radiosurgery to evade the morbidities that accompany surgery. However, some prior studies have not supported this hypothesis. As a radiosurgical counterpart to the Spetzler-Martin grading system, Pollock and Flickinger (40) developed the RBAS, which incorporated patient age, AVM volume, and nidus location into an equation in which each component was mathematically weighted. The RBAS was found to inversely correlate with excellent outcome, defined as complete AVM obliteration without new neurological deficit. The RBAS has been modified twice since its inception without any alteration of the weight given to patient age, and we used the most recent modification for the current study (39, 52). The correlation of RBAS with post-treatment outcomes has not been consistently observed in large AVM radiosurgery series (15, 17, 19, 27, 37, 43, 48). The VRAS, which was developed at our institution to predict favorable outcome (AVM obliteration, no latency period hemorrhage, no permanent RIC) after AVM radiosurgery, did not include patient age, but rather AVM volume, history of hemorrhage, and eloquent nidus location (49). In the current analysis, RBAS was not significantly associated with obliteration nor with RIC, whereas VRAS was an independent predictor of RIC (P ¼ 0.008), but not associated with obliteration. The erratic correlation of RBAS with AVM radiosurgery outcomes suggests that the effect of patient age may be variable across different cohorts. The significantly larger number of isocenters (P ¼ 0.038) used in the radiosurgery treatment plans of the elderly AVM cohort suggests a greater complexity of nidus morphology. Because nidus volume and radiosurgical dose were matched, and thus not significantly different, between the 2 cohorts, we do not believe that a potential imbalance in the complexity of nidus morphology could appreciably affect the major findings of this study. In fact, this suggests that, with radiosurgery, we are able to achieve outcomes in elderly patients with relatively complex AVMs that are equivalent to those of younger patients with potentially more simple nidi. Only higher margin dose was identified as an independent predictor of obliteration (P < 0.0001). We found that AVMs treated with a margin dose of at least 22 Gy had a significantly higher obliteration rate over time (P ¼ 0.001; Figure 2). Flickinger et al. (22) performed a dose-response analysis for AVM radiosurgery and found margin dose, but not nidus volume or maximal dose, correlated with obliteration. In contrast to prior studies, embolization was not associated with reduced AVM obliteration in this analysis (P ¼ 0.896) (4, 7, 15, 19, 24, 34, 41). As the reserve for neurological recovery diminishes with age, adverse events after radiosurgery may be particularly harmful in the elderly population (23). The incidences of radiologically evident (36%) and symptomatic (11%) RIC in the elderly AVM cohort were similar to previously reported rates in larger cohorts, although it should be noted that there were no cases of permanent RIC (54). Prior analyses have found that a larger radiosurgical target volume corresponds to a higher risk of RIC (21). Although nidus volume was significantly associated with RIC in the univariate analysis (P ¼ 0.015), it was not identified as an independent predictor in the multivariate analysis. The annual hemorrhage risk after radiosurgery was 1.1%, and the AVM-related mortality rate was 1.5%. This compares favorably to natural history of AVMs in patients more than 60 years of age

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(5, 29). In addition, the rate of seizure improvement after radiosurgery (62%) was consistent with prior reports, and the incidence of de novo seizures was low (1.9%) (8, 44). Based on the findings of our study, we propose that radiosurgery can effectively treat AVMs in elderly patients with an acceptable safety profile. Many patients more than 60 years of age have 2 or more decades of life ahead. Thus, a treatment for their AVMs that offers reasonable efficacy and safety should be strongly considered; radiosurgery appears to offer just such a treatment profile for elderly patients. The controversy surrounding the optimal management of AVMs has increased considerably after the recent publication of 2 prospective studies, A Randomized Trial of Unruptured Brain AVMs (ARUBA) and the comparative AVM study from the Scottish Audit of Intracranial Vascular Malformations (SAIVM), which reported worse outcomes with intervention than medical management in patients with unruptured AVMs (3, 32). Limitations of these studies included 1) alarmingly high rates of AVM hemorrhage after intervention, suggesting an excess of treatment-related complications and/or incomplete AVM obliteration; 2) use of embolization alone in 20%e30% of patients in the intervention arms, despite the relatively low cure rate of this approach (10%e20%) compared with alternative standalone therapies such as surgical resection (90%e100%) and radiosurgery (60%e80%); and 3) insufficient follow-up durations to realize the long-term benefit of AVM obliteration, specifically freedom from hemorrhage-associated neurological injury (38, 47, 51). Unruptured AVMs comprised only a minority (44%) of our cohort. Furthermore, the age of the patients in our study (mean  SD 67.0  5.4 years) was significantly more advanced than in ARUBA (mean  SD 44  12 years) or the SAIVM AVM study (mean  SD 41  13 years). Thus, the conclusions of both prospective analyses may not be applicable to elderly patients with AVM. Study Limitations The limitations of this study should be noted. First and foremost, this is a retrospective, single-center analysis of 2 matched cohorts of patients who were uniformly treated with radiosurgery. As such, the study is subject to the selection and treatment biases of our institution and physicians. We also lack detailed clinical followup, including information regarding the time from radiosurgery to seizure improvement or de novo seizures, on many of our

REFERENCES

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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 9 February 2015; accepted 13 May 2015

53. Yen CP, Ding D, Cheng CH, Starke RM, Shaffrey M, Sheehan J: Gamma Knife surgery for incidental cerebral arteriovenous malformations. J Neurosurg 121:1015-1021, 2014.

Citation: World Neurosurg. (2015). http://dx.doi.org/10.1016/j.wneu.2015.05.012

54. Yen CP, Matsumoto JA, Wintermark M, Schwyzer L, Evans AJ, Jensen ME, Shaffrey ME, Sheehan JP:

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