Microsurgical Resection for Persistent Arteriovenous Malformations Following Gamma Knife Radiosurgery: A Case-Control Study

Original Article

Microsurgical Resection for Persistent Arteriovenous Malformations Following Gamma Knife Radiosurgery: A Case-Control Study Xianzeng Tong1-4, Jun Wu1-4, Jian Pan5, Fuxin Lin1-4, Yong Cao1-4, Yuanli Zhao1-4, Shuo Wang1-4, Jizong Zhao1-4

OBJECTIVE: To explore outcomes after microsurgery of brain arteriovenous malformations (AVMs) that failed to be obliterated by Gamma Knife radiosurgery (GKRS).

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METHODS: From January 2000 to January 2014, 42 consecutive patients underwent surgical resection of persistent AVMs after GKRS. These 42 patients with AVMs who underwent radiosurgery (radiosurgery group) were individually matched with 42 patients with AVMs who did not undergo radiosurgery (no radiosurgery group) based on patient and AVM characteristics. The modified Rankin Scale was used to assess neurologic status of patients. The effects of GKRS on AVM resection and surgical outcomes were analyzed.

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RESULTS: After GKRS, the mean AVM volume was significantly reduced by 76.8% (P < 0.01), the size was reduced by 41% (P < 0.01), and the Spetzler-Martin grade was reduced in 61.9% of the patients (P < 0.01). During the time interval from radiosurgery to surgical resection, subsequent hemorrhages led to significant neurologic deterioration (P [ 0.046). Compared with the control group, the frequency of preoperative embolization, operative time, and blood loss were significantly lower in the radiosurgery group (all P < 0.05). The no radiosurgery group had a significantly higher rate of worsening in mRS scores at 6 months after surgery (40.5% vs. 16.7%, P [ 0.029). Good neurologic status (mRS score <3) was achieved in 81% of the radiosurgery group and 83% of the no radiosurgery group at the final follow-up evaluation.

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CONCLUSIONS: GKRS performed several years before microsurgical resection can facilitate resectability of AVMs and decrease the rate of postoperative neurologic deterioration. For patients with persistent AVMs several years after GKRS, microsurgical resection is recommended to achieve good clinical outcomes.

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INTRODUCTION

S

urgical resection of brain arteriovenous malformations (AVMs) is challenging in regard to postoperative neurologic deficits, especially for large and complex AVMs in eloquent locations. There are no clear guidelines for choosing the optimal treatment modality for each individual patient with an AVM. Gamma Knife radiosurgery (GKRS) is mainly applied as a single treatment for AVMs that are small (<3 cm diameter), unruptured, or poorly accessible. GKRS may also be recommended as part of multimodal therapy in combination with microsurgical resection and embolization to reduce the size of high-volume AVMs.1,2 In the literature, 5-year obliteration rates after GKRS range from 23% to 94%.3-9 However, there are still a large proportion of incompletely obliterated or persistent AVMs following GKRS. Controversy exists regarding the risk of hemorrhage in persistent AVMs.7,10,11 However, most studies in the literature state that the hemorrhage risk exists as long as the AVM nidus persists.9-15 Treatment options for persistent AVMs after radiosurgery include repeat radiosurgery, surgical resection, endovascular embolization, and observation.3,9,16-18 However, there is no

Key words - Gamma Knife radiosurgery - Microsurgical resection - Persistent arteriovenous malformations

From the 1Department of Neurosurgery, Beijing Tiantan Hospital, and 5Gamma Knife Center, Beijing Neurosurgical Institute, Capital Medical University; 2China National Clinical Research Center for Neurological Diseases; 3Center of Stroke, Beijing Institute for Brain Disorders; and 4 Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China

Abbreviations and Acronyms AVM: Arteriovenous malformation DSA: Digital subtraction angiography GKRS: Gamma Knife radiosurgery mRS: Modified Rankin Scale RSL: No radiosurgery RSD: Radiosurgery S-M: Spetzler-Martin

To whom correspondence should be addressed: Shuo Wang, M.D. [E-mail: [email protected]]

WORLD NEUROSURGERY 88: 277-288, APRIL 2016

Citation: World Neurosurg. (2016) 88:277-288. http://dx.doi.org/10.1016/j.wneu.2016.01.027 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.

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current consensus on the optimal management of persistent AVMs after radiosurgery. The decision to pursue a given modality of retreatment must be based on the characteristics of the AVM after radiosurgery, the patient’s clinical symptoms, the perceived hemorrhage risk, the obliteration rate, and treatment-related complications.3 In a recent review of the literature by Awad et al.,3 repeat radiosurgery obliterated 61% of persistent AVMs. The most common complications included hemorrhage during the latency period in 7.6% and radiation-induced changes in 7.4%. Compared with repeat radiosurgery, surgical resection of persistent AVMs is less frequently reported,19-25 and only 3 studies reported >20 cases.21,23,24 Biologic changes in the arteries induced by radiosurgery include intimal hyperplasia, medial hyalinization, wall thickening, and subsequent lumen narrowing or obliteration.23,26 These biologic changes brought about by radiosurgery can facilitate AVM resection during surgery.20,23-25 After radiosurgery, AVMs may become less vascular.20,23,24 Preoperative embolization may be used less.23 Radiosurgery effects may create gliotic planes adjacent to the AVMs to improve dissection during resection. Blood loss, operative time, and hospital stay may decrease significantly.23 However, in the literature, only 1 study by Sanchez-Mejia et al.23 quantified the surgical advantages of radiated AVMs. Conflicts also exist regarding the surgical advantages offered by AVM radiosurgery. In 2009, Asgari et al.19 found that AVMs incompletely obliterated by radiosurgery bear an increased surgical risk. A more complicated AVM morphology was revealed by angiographic studies. The authors also found that microsurgical resection was extremely challenging and led to unfavorable outcomes in many patients.19 In this study, we performed a retrospective analysis of 42 patients who were surgically treated for AVMs several years after GKRS. The patients were matched individually with 42 patients who were surgically treated for AVMs without prior radiosurgery. The radiosurgical effects on AVM features, surgical resection, and neurologic outcomes were analyzed and discussed. In this casecontrol study, we hypothesized that good clinical outcomes can be achieved by surgical resection of persistent AVMs several years after GKRS. MATERIALS AND METHODS Patients This study was approved by the institutional review board of Beijing Tiantan Hospital Affiliated to Capital Medical University. The prospectively maintained AVM database at Beijing Tiantan Hospital was searched to identify patients who underwent microsurgery to treat incompletely obliterated brain AVMs after GKRS between January 2000 and January 2014. Patients meeting the following criteria were included: 1) patients treated with microsurgical resection for persistent brain AVMs after GKRS; 2) patients with a definite diagnosis of persistent AVMs after GKRS confirmed by preoperative digital subtraction angiography (DSA) and postoperative pathologic examination; and 3) patients with sufficient clinical, radiologic, radiosurgical, and follow-up data. The following patients were excluded: 1) patients treated with microsurgical resection for persistent brain AVMs after other types of radiotherapy (e.g., helium ion, proton beam, linear

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accelerator); 2) patients with other types of vascular malformations, such as cavernous malformations, revealed by postoperative pathology; 3) patients with insufficient clinical, radiologic, and radiosurgical data; and 4) patients lost to follow-up after microsurgical treatment. Of the 1726 patients with AVMs surgically treated during the period 2000e2014, 42 consecutive patients with sufficient data were included in the study. The baseline patient characteristics (sex, age, history) and AVM features (size, side, location, angioarchitecture, Spetzler-Martin [S-M] grade) were collected. The time span between GKRS and surgical resection was recorded. For this case-control study, the matching was performed independently by an observer blinded to postoperative neurologic outcomes. We used a case-matching method similar to the one described by Sanchez-Mejia et al.23 in their study of AVM surgical outcome after radiosurgery. The 42 patients with prior radiosurgery (RSþ) were individually matched with 42 patients with no radiosurgery (RS) based on the following criteria: patient age, AVM size, location, diffuseness, deep venous drainage, S-M grade, hemorrhagic presentation, and modified Rankin Scale (mRS) scores at diagnosis (Table 1). All these criteria may affect the neurologic outcomes after AVM resection. Gamma Knife Radiosurgery Treatment GKRS was chosen based on the following factors: clinical presentation, AVM characteristics, functional status, and patient preference. Generally, GKRS is indicated as a single treatment for AVMs that are small (<3 cm diameter), unruptured, or poorly accessible. For high-volume AVMs, GKRS is also indicated as part of multimodal therapy in combination with microsurgical resection and embolization to reduce the AVM size. GKRS is also indicated for AVMs that are located in eloquent regions associated with high surgical risks. The patients were treated with the Leksell Gamma Knife (Elekta AB, Stockholm, Sweden) at the Radiosurgical Center of our institution. The mean irradiated AVM volume was 40,000 mm3 (range, 1000e83,100 mm3). The mean maximum dose was 38 Gy (range, 28e50 Gy). The mean marginal dose at the 50% isodose line was 20 Gy (range, 16e25 Gy). The mean radiation time was 36 minutes (range, 20e80 minutes). The patients were followed clinically at least every 6 months after radiosurgery. After GKRS, magnetic resonance imaging was performed at 3-month intervals in the first year, at 6-month intervals in the following 2 years, and then on a yearly basis. Follow-up DSA was performed to confirm AVM obliteration 3e4 years after GKRS. The patient’s neurologic status was assessed with mRS. Subsequent AVM hemorrhages and complications after radiosurgery were recorded. Microsurgical Treatment Preoperative embolization was considered to facilitate surgical resection in 10 cases in RSþ group. Microsurgical AVM resection was performed in RSþ patients at the following times after GKRS: 1 year (3 patients), 2 years (5 patients), 3 years (4 patients), 4 years (8 patients), 5 years (3 patients), 6 years (6 patients), 7 years (4 patients), 8 years (4 patients), 9 years (2 patients), 10 years (1 patient), 11 years (1 patient), and 13 years (1 patient). The reasons for surgical resection were subsequent hemorrhages and

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ORIGINAL ARTICLE XIANZENG TONG ET AL.

MICROSURGICAL RESECTION OF RADIATED AVMS

Table 1. Baseline Clinical Data of Patient Groups at Initial Presentation RSD (n [ 42)

RSL (n [ 42)

Male

28 (66.7%)

26 (61.9%)

Female

14 (33.3%)

16 (38.1%)

Age, years (mean  SD)

20.8  10.6

20.5  10.7

Nonhemorrhage

23 (54.8%)

23 (54.8%)

Hemorrhage

19 (45.2%)

19 (45.2%)

Left

24 (57.1%)

20 (47.6%)

Right

18 (42.9%)

22 (52.4%)

Parameters

P Value

Sex

0.820

Presentation

1.000

AVM laterality

0.512

AVM size <3 cm 3, <6 cm 6 cm

1.000 6 (14.3%)

7 (16.7%)

36 (85.7%)

35 (83.3%)

0

0

Venous drainage

1.000

Superficial only

24 (57.1%)

23 (54.8%)

Deep

18 (42.9%)

19 (45.2%)

Diffuse

19 (45.2%)

16 (38.1%)

Compact

23 (54.8%)

26 (61.9%)

Noneloquent

11 (26.2%)

11 (26.2%)

Eloquent

31 (73.8%)

31 (73.8%)

Diffuseness

0.658

Eloquence

Statistical Analysis Statistical analyses were performed with SPSS version 20.0 (SPSS, Inc., Chicago, Illinois, USA). Patient demographics, AVM characteristics, intraoperative and postoperative results, and neurologic status were summarized using descriptive statistics for continuous variables (mean  SD, minimum and maximum) and categorical variables (count and percentage). Subgroup analyses were performed using independent sample t-test for continuous variables and c2 test or Fisher exact test for categorical variables. For such variables as S-M grade and mRS scores, both the independent sample t-test and the nonparametric test were used. Subgroup comparisons were performed for baseline data between RSþ and RS patients, AVM features before and after GKRS, and operative outcomes between RSþ and RS patients. Statistical significance was established at P value < 0.05.

1.000

S-M grade I

0.870

symptomatic deterioration. In our study, surgical resection of AVMs was performed by a single author (S.W.). After AVM resection, the patients had follow-up evaluations at 6 months, 12 months, and then on a yearly basis. The follow-up data were obtained through telephone interviews or routine clinical visits. We used the following measures to evaluate the outcomes: obliteration rate, postoperative hemorrhage, seizure control, surgery-related complications, and mRS scores. AVM obliteration was assessed by postoperative DSA or computed tomography angiography, which was routinely done during the early postoperative period (3e7 days after surgery). Good functional status was defined as mRS score <3 at the final follow-up, and poor functional status was defined as a final mRS score 3. Neurologic improvement was defined as a decrease in mRS score after surgery compared with the presurgical state. Neurologic deterioration was an increase in mRS score.

RESULTS

1.000 0

0

II

8 (19.0%)

8 (19.0%)

III

25 (59.5%)

25 (59.5%)

IV

9 (21.4%)

9 (21.4%)

V

0

0

mRS score at diagnosis

1.000

0

7 (16.7%)

7 (16.7%)

1

20 (47.6%)

20 (47.6%)

2

9 (21.4%)

9 (21.4%)

3

4 (9.5%)

4 (9.5%)

4

2 (4.8%)

2 (4.8%)

5

0

0

Values are number (%) except where noted. RSþ, radiosurgery; RS, no radiosurgery; AVM, arteriovenous malformation; S-M, Spetzler-Martin; mRS, modified Rankin Scale.

WORLD NEUROSURGERY 88: 277-288, APRIL 2016

Baseline Characteristics of RSD and RSL Patients The baseline characteristics of the RSþ and RS patients are listed in Table 1. For RSþ patients, mean age at presentation was 20.8 years (range, 1e43 years). Mean age at surgical resection was 27.9 years (range, 6e56 years). The mean time interval between GKRS and surgical resection was 60.7 months (range, 12e156 months). The 2 patient groups were matched well in factors that may influence the surgical outcomes of AVM patients, especially in patient age, presentation of hemorrhage, AVM size, venous drainage, eloquent location, S-M grade, and mRS scores at diagnosis (Table 1). Changes in AVM Features After Radiosurgery Table 2 shows the changes of AVM volume, size and S-M grade after GKRS. Compared with the average AVM volume at diagnosis, the average AVM volume after radiosurgery was significantly reduced by 76.7% (9.3 cm3 vs. 40 cm3, P < 0.01) (Table 2 and Figures 1 and 2). The average AVM size was reduced by 41% (24.5 mm vs. 41.5 mm, P < 0.01) (Table 2 and Figures 1 and 2). This reduction in AVM size downgraded S-M scores in 26 (61.9%) of 42 RSþ patients (P < 0.01), and all 26 patients had a decrease in grade by 1 point. Likewise, the

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Table 2. Changes of Arteriovenous Malformation Features After Gamma Knife Radiosurgery Parameters

At Diagnosis

After GKRS

P Value

AVM volume, cm3 (mean  SD)

40.0  24.6

9.3  8.3

< 0.01

AVM size, mm (mean  SD)

41.5  10.7

24.5  7.4

< 0.01 < 0.01

S-M grade, number (%) I

0

3 (7.1%)

II

8 (19.0%)

22 (52.4%)

III

25 (59.5%)

14 (33.3%)

IV

9 (21.4%)

3 (7.1%)

V

0

0

Average S-M score (mean  SD)

3.0  0.6

2.4  0.7

< 0.01

GKRS, Gamma Knife radiosurgery; AVM, arteriovenous malformation; S-M, SpetzlerMartin.

average S-M score was reduced by 20% after radiosurgery before resection (2.4 vs. 3.0, P < 0.01) (Table 2). The decrease in S-M grade was due to the reductions in size after radiosurgery. We did not find any occlusion of deep draining veins after radiosurgery, which is also an influencing factor of AVM S-M grade. As Table 2 shows, GKRS significantly reduced AVM size and concurrently downgraded S-M scores in a large proportion of patients. Hemorrhage Episode After GKRS As can be concluded from Figure 3, during the time interval between radiation and resection, 17 patients experienced subsequent hemorrhages in 212.6 patient-years. The overall annual hemorrhage rate for persistent AVMs after GKRS was 8%. By the time point of 3 years after GKRS, 4 hemorrhages occurred in 112.5 patient-years, and the annual hemorrhage rate for all 42 patients was 3.6%. There were 30 patients who underwent surgical resection beyond the 3-year latency period. Beyond this latency, 13 hemorrhages occurred in 100.1 patient-years, and the annual bleeding rate was 13%. There was a significant increase in bleeding risk after the 3-year latency period. Hemorrhages occurring after radiosurgery led to neurologic deterioration in 11 patients. Effect of GKRS on AVM Surgical Resection Table 3 shows the comparison of operative results between the RSþ and RS patient groups. Preoperative embolization was performed in 10 (24%) RSþ patients and in 22 (52%) RS patients. This difference was statistically significant (P ¼ 0.013) (Table 3). This result implied that radiosurgery reduced the use of preoperative embolization by 55%. GKRS facilitated AVM surgical resection. During surgery, AVMs in RSþ patients were less vascular and easy to resect. The average blood loss during surgery was 563 mL in RSþ patients and 825 mL

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in RS patients. Radiosurgery reduced the average blood loss by 32% compared with the blood loss in RS patients (P < 0.01). The average operative time between RSþ and RS patients showed a significant difference (210 minutes vs. 232 minutes, P ¼ 0.014). Radiosurgery reduced the average operative time by 9.5% compared with operative time in RS patients. AVM Obliteration, Hemorrhages, and Seizure Control After Surgical Resection As revealed by postoperative DSA or computed tomography angiography, all AVMs in RSþ and RS patients were completely obliterated (Figures 1 and 2). Postoperative hemorrhages occurred in 2 RSþ patients and 5 RS patients. These hemorrhages did not necessitate a second operation. At the final follow-up evaluation, a modified Engel class I outcome (complete freedom from seizures or only 1 postoperative seizure) was observed in 75% of the 16 RSþ patients and 80% of the 15 RS patients who presented with seizure at diagnosis. Among the remaining 7 patients with pretreatment seizures, 3 in the RSþ group and 1 in the RS group had seizures medically controlled during the follow-up. De novo seizure occurred in 5 patients after treatment (3 in the RS group and 2 in the RSþ group). De novo seizures were medically controlled during follow-up. Neurologic Outcomes After Surgical Resection Baseline mRS scores at diagnosis in RSþ and RS patients were well matched, as illustrated in Table 1 and Figures 4 and 5. Figure 4 illustrates mRS assessment of RSþ and RS patients at 4 time points: at diagnosis, before surgical resection, 6 months after surgery, and at the final follow-up. Figure 5 shows the average mRS scores at the 4 time points. During the time interval from AVM diagnosis to surgical resection, RSþ patients experienced significant changes in mRS scores (Figure 4). The average mRS score in RSþ patients increased from 1.38 at diagnosis to 1.86 before surgical resection (Figure 5). This difference was statistically significant (P ¼ 0.046). The increase of average mRS scores was largely due to subsequent hemorrhages during the time interval. In contrast, RS patients experienced minor, insignificant changes during this time interval (Figures 4 and 5). Only 3 patients experienced an increase of 1 point in mRS scores, owing to intractable seizures and progressive neurologic deficits. No RS patients experienced further hemorrhages before surgical resection. The time interval from diagnosis to surgical resection for RS patients was 1e6 months, which was a much shorter time interval than for RSþ patients. At 6 months after surgical resection, mRS scores were statistically similar for the RSþ and RS groups (Figure 4). The average mRS score was also statistically similar (1.93 vs. 1.95, P ¼ 0.919) (Figure 5). The RS patients experienced a significant increase in mRS scores compared with their presurgical state (Figure 4). The average mRS score increased significantly from 1.45 before surgical resection to 1.95 at 6 months after surgery (P ¼ 0.034) (Figure 5). The RSþ patients also experienced an increase in average mRS scores; however, the difference did not reach statistical significance (P ¼ 0.300) (Figures 4 and 5). At 6 months after surgical resection, compared with the presurgical state, 7 patients in the RSþ group and 17 patients in the

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ORIGINAL ARTICLE XIANZENG TONG ET AL.

MICROSURGICAL RESECTION OF RADIATED AVMS

Figure 1. Case 1. (A) Before Gamma Knife radiosurgery (GKRS), T2-weighted magnetic resonance imaging demonstrating a right temporal arteriovenous malformation (AVM) in a 31-year-old man with a history of epileptic seizure. (B) T2-weighted magnetic resonance imaging performed 7 years after GKRS showing significant decrease in AVM size. (C and D) Preoperative anteroposterior angiographic views of the right carotid artery and right vertebral artery demonstrating the persistent AVM nidus after GKRS. (E and F) Postoperative anteroposterior angiographic views of the right carotid artery and right vertebral artery demonstrating no evidence of residual right temporal AVM after microsurgical resection.

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Figure 2. Case 10. (A and B) Before Gamma Knife radiosurgery, anteroposterior and lateral angiographic views of the left carotid artery demonstrating a left temporoparietal arteriovenous malformation (AVM) in a 6-year-old boy with a history of hemorrhage. (C and D) Anteroposterior and lateral angiographic views of the left carotid artery obtained 6 years after Gamma Knife radiosurgery demonstrating downsized yet persistent AVM nidus. (E and F) Anteroposterior and lateral angiographic views of the left carotid artery obtained after microsurgical resection demonstrating no evidence of residual left temporoparietal AVM.

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ORIGINAL ARTICLE XIANZENG TONG ET AL.

MICROSURGICAL RESECTION OF RADIATED AVMS

Figure 3. Annual hemorrhage rate in the radiosurgery (RSþ) patients during the time interval between Gamma Knife radiosurgery and surgical resection.

RS group experienced neurologic deterioration (increase in mRS score; P ¼ 0.029) (Table 3). The mean  SD follow-up period was 55.4 months  34.3 for RSþ patients and 58.6 months  29.8 for RS patients (P ¼ 0.655). At the final follow-up evaluation, mRS scores in both the RSþ and the RS groups decreased back toward the patients’ initial neurologic status at diagnosis. The neurologic outcomes were statistically similar for the 2 groups regarding the mRS score distribution (Figure 4) and the average mRS score (1.40 vs. 1.50, P ¼ 0.679) (Figure 5). Overall, a statistically similar rate of good neurologic status (mRS score <3) was achieved in the RSþ and RS groups (81% vs. 83%). DISCUSSION Management of eloquent or high S-M grade brain AVMs is challenging. Current treatment modalities include microneurosurgical resection, endovascular intervention, and radiosurgery alone or in

Table 3. Comparison of Operative Results Between Patient Groups Parameters

RSD

RSL

Without embolization

32

20

With embolization

10

22

Preoperative embolization (n)

P Value 0.013

Blood loss, mL (mean  SD)

563  264

825  322

Operative time, minutes (mean  SD)

210  43

232  40

Improved or unchanged

35

25

Worsening

7

17

Postoperative neurologic status (n)

< 0.01 0.014 0.029

RSþ, radiosurgery; RS, no radiosurgery.

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combination. The goal of treatment is complete obliteration of an AVM. However, we still do not have clear guidelines for reference to choose an optimal treatment modality for each individual patient with an AVM. According to the literature and our experience, endovascular therapy should mainly be used for preoperative embolization and should not be considered a curative modality for brain AVM treatment, whereas radiosurgery should mainly be used for poorly accessible, deep-seated grade III brain AVMs, requiring a lag time of several years for radiation-induced obliteration.8 In the literature, AVM obliteration rates are 23%e94% after GKRS.3,9 A meta-analysis of 13,698 patients with brain AVMs by van Beijnum et al.27 showed an obliteration rate of 96% by microsurgical resection, 38% by stereotactic radiosurgery, and 13% by endovascular embolization. It has been widely accepted that patients with incompletely obliterated AVMs remain at risk for hemorrhage whether after microsurgery, embolization, or radiosurgery.8,13-15,28 Microsurgical management of persistent AVMs after radiosurgery is reported in only a few studies (Table 4).19-25 In this study with limited cases, we did not intend to recommend GKRS for large AVMs. As can be concluded from our results, good outcome can also be achieved by microsurgical resection of AVMs in RS patients. However, high rates of good outcomes are based on neurosurgical center experience with management of AVMs. We performed this study simply to demonstrate that persistent AVMs several years after GKRS can be managed with surgical resection to achieve good clinical outcomes.

Case-Control Matching in Study In this study, case matching was performed on the basis of patient characteristics and AVM angioarchitecture at the time of diagnosis before any treatment. Some investigators may argue that the matching should be based on patient and AVM features at the time of surgical resection, considering the downgraded AVMs by GKRS. They may argue that this study is actually comparing the surgical outcomes between higher grade AVMs (RS) and lower

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Figure 4. Neurologic status (modified Rankin Scale scores) of radiosurgery (RSþ) patients (upper panel) and no radiosurgery (RS) patients (lower panel) at 4 different time points: at diagnosis, after Gamma Knife radiosurgery and before surgical resection, 6 months after resection, and at the final follow-up.

grade AVMs (RSþ). From their viewpoint, matching for patient and AVM features at the time of surgery would be more reflective of the potential impact of prior radiosurgery on surgical risks and outcome. We realized this issue in the process of designing the study. On the basis of the literature, we chose to use a similar case-matching method as described in the study by Sanchez-Mejia et al.,23 who performed a case-control study to compare the surgical result of RSþ and RS patients. Postradiosurgical AVMs Facilitate Surgical Resection Biologic changes in AVM arteries induced by GKRS include intimal hyperplasia, creation of intraluminal myofibroblasts, medial hyalinization, and wall sclerosis.24,26,29,30 These changes

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lead to progressive luminal thrombosis and subsequent lumen narrowing or obliteration. Thus, radiosurgery induces a slow obliterative process that resembles atherosclerosis. This process can progressively obliterate some AVMs or at least decrease the AVM volume. In our series, the average AVM volume was decreased by 76.7%, and the average AVM size was reduced by 41%. The reduced AVM size significantly downgraded the average AVM S-M score. Our results were similar to the results of the study by Sanchez-Mejia et al.23 In their study, the average AVM volume was reduced by 78%, and AVM S-M grades were reduced in 52% of patients after radiosurgery.23 Thus, the biologic effects induced by GKRS changed AVM S-M grades from high scores to more intermediate scores that are favorable for surgical resection.

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ORIGINAL ARTICLE XIANZENG TONG ET AL.

MICROSURGICAL RESECTION OF RADIATED AVMS

Effect of Prior Radiosurgery on Neurologic Status Generally, previous studies showed that good outcomes can be achieved by surgical resection of persistent AVMs after radiosurgery (Table 4).20-25 Excellent or good clinical outcome was achieved in 94% of the patients in the study by Steinberg et al.24 (Table 4). However, postoperative angiography revealed residual AVM nidus in 15% of the patients, and 2 patients died of fatal repeat hemorrhages.24 In our series, good outcome was achieved in 81% of the patients at the final follow-up. All the AVMs in our study were completely obliterated after surgical resection. Although hemorrhage as a surgery-related complication occurred in 2 RSþ patients immediately after surgery, no patients died during our follow-up period. In the study by Asgari et al.,19 neurologic deterioration occurred in 3 (38%) of 8 patients after surgical resection. The reason may be that the mean preoperative mRS score in their series was higher than in our series (2.75 vs. 1.86) and that the radiosurgical advantage was not as prominent as in our series. In the study by Sanchez-Mejia et al.,23 for RS patients, the mRS score distribution before resection was statistically similar to that at diagnosis. For RSþ patients, during the time interval between diagnosis and surgical resection, the mRS score increased significantly because of subsequent hemorrhages in some patients. Our findings are consistent with those findings. The RSþ and RS patients were individually matched. The RSþ patients experienced a significant increase in mRS scores because of repeat hemorrhages after diagnosis before surgical resection, whereas the RS patients did not experience a significant increase in mRS scores. In contrast, the RS patients experienced a significant increase in mRS scores after surgical resection compared with their presurgical state, whereas the RSþ patients did not. At 6 months after surgery, compared with preoperative neurologic status, neurologic deterioration (increase in mRS score) occurred in 16.7% of RSþ patients and 40.5% of RS patients; this can be ascribed to the above-described radiosurgical advantages. Although the RS patients experienced a higher rate of neurologic deterioration at 6 months after surgery, the mRS score

Figure 5. Average modified Rankin Scale (mRS) scores of radiosurgery (RSþ) patients and no radiosurgery (RS) patients at 4 different time points: at diagnosis, after Gamma Knife radiosurgery and before surgical resection, 6 months after resection, and at the final follow-up.

AVMs are less vascular after radiosurgery, and this is another factor that facilitates surgical resection. In our series, the AVMs in RSþ patients were less vascular and easier to resect compared with the AVMs in RS patients. Our findings were consistent with previous studies.23-25 We also found that radiation-induced gliotic planes adjacent to the AVMs improved surgical dissection during resection. These biologic factors induced by GKRS accounted for less preoperative embolization, shorter operative time, and reduced blood loss. However, conflict exists regarding the advantages of radiosurgery for subsequent surgical resection. In the study by Asgari et al.,19 radiation treatment was associated with more difficulties in subsequent resection. The AVMs were found to be highly vascular, and surgical resection was complicated by firm tissue consistency. These factors led to more preoperative embolization, significant blood loss (mean 1500 mL), and a high rate of neurologic deterioration. The authors ascribed the different results to 2 main reasons: eloquent location of all AVMs and relatively lower average radiation doses.19 However, this assumption warrants further studies.

Table 4. Published Reports of Patients with Surgically Resected Arteriovenous Malformations That Were Incompletely Obliterated by Prior Radiosurgery AVM S-M Grade Number of Patients

I

II

III

IV

V

Time Interval, Years (mean)*

Steinberg et al., 199624

33

0

1

12

16

4

4.4

Firlik et al., 199822

1

0

0

0

0

0

3

GKRS

100

Sanchez-Mejia et al., 200923

21

1

2

8

10

0

4.7

GKRS

76

Asgari et al., 2009

8

0

0

5

3

0

7

Proton beam, GKRS, conventional

Zaidi et al., 201325

1

0

0

0

0

1

3

GKRS

Choudhri, et al., 201521

84

3

10

26

33

12

NA

Helium ion, proton beam, GKRS, LA

81

Present study

42

0

8

25

9

0

5.1

GKRS

81

Study

19

Radiation Type

Good Clinical Outcome (%)

Helium ion, proton beam, GKRS, LA

94

62 100

AVM, arteriovenous malformation; S-M, Spetzler-Martin; GKRS, Gamma Knife radiosurgery; LA, linear accelerator; NA, not available. *The time interval between radiation and resection.

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distribution and mean mRS scores in the 2 groups were statistically similar at 6 months after surgery and at the final follow-up. Our findings are consistent with the study by Sanchez-Mejia et al.23 These changes in mRS score suggest that the biologic advantages offered by GKRS were offset by AVM hemorrhages during the time interval between radiation and resection. Ultimately, similar neurologic status was achieved in RSþ and RS patients. In our series, at the final follow-up, the mRS score distribution in both RSþ and RS patients tended to be similar to the patients’ initial state at diagnosis. However, in the study by Sanchez-Mejia et al.,23 the mean mRS scores were significantly higher than in our series both at 6 months after surgery and at the final follow-up. Their series did not show a tendency toward the initial pretreatment state. Hemorrhage Risk After GKRS In the literature, some studies found that the risk of hemorrhage was reduced after GKRS before AVM obliteration.7,11 However, some larger studies demonstrated that the annual risk of hemorrhage for persistent AVMs after GKRS was still comparable to that of natural history.12,15,18 Regardless of the debate whether radiosurgery modifies the natural history of hemorrhage during or beyond the latency period,14,31,32 any persistent AVM nidus has the ongoing potential for hemorrhage. In our series, 17 (40%) of the 42 RSþ patients experienced hemorrhages after radiosurgery, and 13(76%) hemorrhages occurred beyond the 3-year latency period. The annual hemorrhage rate for incompletely obliterated AVMs after GKRS was 8%. The annual hemorrhage rates during and beyond the 3-year latency

period were 3.6% and 13%, respectively. Our results demonstrated that there was a significant increase in hemorrhage risk after the 3-year latency period. The previous study by Sanchez-Mejia et al.23 also found that 71% of hemorrhages after radiosurgery occurred well beyond the latency period. The authors assumed that the high bleeding rate was ascribed to changes in AVM drainage after radiosurgery. However, in our series, no deep draining veins were occluded by radiation. Other, still unknown biologic changes and resultant intranidal hemodynamics may be responsible for the higher hemorrhage rate after radiosurgery. However, we agree with Sanchez-Mejia et al. that the AVM bleeding tendencies might have been changed after radiosurgery; this could explain the high bleeding rate of the AVMs in our series beyond the 3-year latency after GKRS. These 17 hemorrhages accounted for the significant increase in mRS score after radiosurgery before resection compared with the initial mRS score at diagnosis. Readers should not be misled by our results, as patients in our series merely represented patients who underwent surgical resection after radiosurgery. This annual hemorrhage rate cannot be generalized to the population as a whole who harbored incompletely obliterated AVMs after radiosurgery. The annual hemorrhage rate in our study may be higher than that in the whole radiated population. Timing and Indications of Surgical Resection for Persistent AVMs After GKRS In our series, radiosurgery significantly decreased AVM volume, reduced S-M grades, and made AVMs less vascular. These changes are favorable for surgical resection. Surgical results were excellent

Figure 6. Recommended treatment algorithm for arteriovenous malformations (AVMs) after Gamma Knife radiosurgery (GKRS).

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MICROSURGICAL RESECTION OF RADIATED AVMS

with less embolization, reduced blood loss, decreased operative time, and good neurologic status. However, considering the increased hemorrhage rate and resultant neurologic deterioration beyond the 3-year latency period, we suggest early surgical resection of incompletely obliterated AVMs after GKRS (Figure 6). The average time interval between radiation and resection in our study was 5.1 years, during which 11 patients experienced neurologic deterioration because of the 13 hemorrhages beyond the 3-year latency period. The previous study by Sanchez-Mejia et al.23 showed that 3-year latency periods maximize the biologic response of an AVM. Early surgical resection at the end of or just beyond the 3-year latency period may take advantage of favorable biologic changes offered by GKRS, avoid postradiosurgical hemorrhages beyond the latency period, and further improve the patient’s neurologic status. Just as Sanchez-Mejia et al.23 stated, surgical resection should be timed to allow the AVM to respond fully to radiation but should not incur the hemorrhage risk from delay beyond the latency period. However, similar to the management of unruptured AVMs, the management of persistent AVMs after GKRS remains uncertain. For persistent AVMs after GKRS, repeated GKRS is an established and well-documented treatment option.9,16,17,33 However, the AVM obliteration rate of repeated radiosurgery varied with different studies. A recent review of the literature showed that repeat radiosurgery can obliterate 61% of persistent AVMs.3 The most common complications included hemorrhage during the latency period in 7.6% and radiation-induced changes in 7.4%. Generally, the indications for microsurgical resection of persistent AVMs after GKRS were hemorrhages, intractable seizures, and neurologic deterioration.19,24 In our series, the indications for AVM resection after GKRS were subsequent hemorrhages (40.5%), intractable epileptic seizures (35.7%), and progressive neurologic deficits

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(23.8%). For patients without worsening symptoms several years after radiosurgery, it is difficult to decide on further management of radiologically persistent AVMs. It is also a difficult decision regarding the timing of surgical resection of these incompletely obliterated AVMs after GKRS, even though subsequent hemorrhage might occur. Based on our study, we recommend early surgical resection of remaining AVMs to avoid further hemorrhages and improve neurologic status (Figure 6). However, for AVMs completely in eloquent areas, surgical resection may be associated with many morbidities. Treatment alternatives are repeat radiosurgery and conservative observation (Figure 6). Limitations This is a small, retrospective study on the microsurgical outcomes of incompletely obliterated AVMs several years after GKRS. Although the case-control study was well matched, there may be selection bias. Selection bias also exists when we calculate the annual hemorrhage rate of AVMs after radiosurgery, which may be misleading to readers. Although we recommend surgical resection for remaining AVMs at the end of or just beyond the 3-year latency period after GKRS, prospective, well-designed studies are warranted to validate our findings. CONCLUSIONS GKRS can induce biologic changes that lead to reduced AVM volume and S-M grade. GKRS performed several years before microsurgical resection can facilitate AVM resectability and decrease the rate of postoperative neurologic deterioration. For patients with incompletely obliterated AVMs several years after GKRS, microsurgical resection is recommended to achieve good clinical outcomes.

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31. Friedman WA, Blatt DL, Bova FJ, Buatti JM, Mendenhall WM, Kubilis PS. The risk of hemorrhage after radiosurgery for arteriovenous malformations. J Neurosurg. 1996;84:912-919.

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Conflict of interest statement: This study was supported by Key Projects in the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period (Grant No. 2011BAI08B08). Received 13 November 2015; accepted 4 January 2016 Citation: World Neurosurg. (2016) 88:277-288. http://dx.doi.org/10.1016/j.wneu.2016.01.027 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.

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