Stereotactic radiosurgery for pediatric brain arteriovenous malformations: long-term outcomes

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  • 1 Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia;
  • | 2 Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital;
  • | 3 School of Medicine, National Yang-Ming University, Taipei, Taiwan;
  • | 4 Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania;
  • | 5 Department of Neurosurgery, University of Louisville School of Medicine, Louisville, Kentucky;
  • | 6 Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, Ohio;
  • | 7 Department of Neurosurgery, New York University Langone Medical Center, New York, New York;
  • | 8 Division of Neurosurgery, Centre de recherché du CHUS, University of Sherbrooke, Sherbrooke, Quebec, Canada;
  • | 9 Department of Radiation Oncology, Beaumont Health System, Royal Oak, Michigan; and
  • | 10 Section of Neurological Surgery, University of Puerto Rico, San Juan, Puerto Rico
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OBJECTIVE

Contrary to the better described obliteration- and hemorrhage-related data after stereotactic radiosurgery (SRS) of brain arteriovenous malformations (AVMs) in pediatric patients, estimates of the rarer complications, including cyst and tumor formation, are limited in the literature. The aim of the present study was to assess the long-term outcomes and risks of SRS for AVMs in pediatric patients (age < 18 years).

METHODS

The authors retrospectively analyzed the International Radiosurgery Research Foundation pediatric AVM database for the years 1987 to 2018. AVM obliteration, post-SRS hemorrhage, cyst formation, and tumor formation were assessed. Cumulative probabilities, adjusted for the competing risk of death, were calculated.

RESULTS

The study cohort comprised 539 pediatric AVM patients (mean follow-up 85.8 months). AVM obliteration was observed in 64.3% of patients, with cumulative probabilities of 63.6% (95% CI 58.8%–68.0%), 77.1% (95% CI 72.1%–81.3%), and 88.1% (95% CI 82.5%–92.0%) over 5, 10, and 15 years, respectively. Post-SRS hemorrhage was observed in 8.4% of patients, with cumulative probabilities of 4.9% (95% CI 3.1%–7.2%), 9.7% (95% CI 6.4%–13.7%), and 14.5% (95% CI 9.5%–20.5%) over 5, 10, and 15 years, respectively. Cyst formation was observed in 2.1% of patients, with cumulative probabilities of 5.5% (95% CI 2.3%–10.7%) and 6.9% (95% CI 3.1%–12.9%) over 10 and 15 years, respectively. Meningiomas were observed in 2 patients (0.4%) at 10 and 12 years after SRS, with a cumulative probability of 3.1% (95% CI 0.6%–9.7%) over 15 years.

CONCLUSIONS

AVM obliteration can be expected after SRS in the majority of the pediatric population, with a relatively low risk of hemorrhage during the latency period. Cyst and benign tumor formation after SRS can be observed in 7% and 3% of patients over 15 years, respectively. Longitudinal surveillance for delayed neoplasia is prudent despite its low incidence.

ABBREVIATIONS

AVM = arteriovenous malformation; EBRT = external-beam radiation therapy; IRRF = International Radiosurgery Research Foundation; RIC = radiation-induced change; SM = Spetzler-Martin; SRS = stereotactic radiosurgery.

OBJECTIVE

Contrary to the better described obliteration- and hemorrhage-related data after stereotactic radiosurgery (SRS) of brain arteriovenous malformations (AVMs) in pediatric patients, estimates of the rarer complications, including cyst and tumor formation, are limited in the literature. The aim of the present study was to assess the long-term outcomes and risks of SRS for AVMs in pediatric patients (age < 18 years).

METHODS

The authors retrospectively analyzed the International Radiosurgery Research Foundation pediatric AVM database for the years 1987 to 2018. AVM obliteration, post-SRS hemorrhage, cyst formation, and tumor formation were assessed. Cumulative probabilities, adjusted for the competing risk of death, were calculated.

RESULTS

The study cohort comprised 539 pediatric AVM patients (mean follow-up 85.8 months). AVM obliteration was observed in 64.3% of patients, with cumulative probabilities of 63.6% (95% CI 58.8%–68.0%), 77.1% (95% CI 72.1%–81.3%), and 88.1% (95% CI 82.5%–92.0%) over 5, 10, and 15 years, respectively. Post-SRS hemorrhage was observed in 8.4% of patients, with cumulative probabilities of 4.9% (95% CI 3.1%–7.2%), 9.7% (95% CI 6.4%–13.7%), and 14.5% (95% CI 9.5%–20.5%) over 5, 10, and 15 years, respectively. Cyst formation was observed in 2.1% of patients, with cumulative probabilities of 5.5% (95% CI 2.3%–10.7%) and 6.9% (95% CI 3.1%–12.9%) over 10 and 15 years, respectively. Meningiomas were observed in 2 patients (0.4%) at 10 and 12 years after SRS, with a cumulative probability of 3.1% (95% CI 0.6%–9.7%) over 15 years.

CONCLUSIONS

AVM obliteration can be expected after SRS in the majority of the pediatric population, with a relatively low risk of hemorrhage during the latency period. Cyst and benign tumor formation after SRS can be observed in 7% and 3% of patients over 15 years, respectively. Longitudinal surveillance for delayed neoplasia is prudent despite its low incidence.

ABBREVIATIONS

AVM = arteriovenous malformation; EBRT = external-beam radiation therapy; IRRF = International Radiosurgery Research Foundation; RIC = radiation-induced change; SM = Spetzler-Martin; SRS = stereotactic radiosurgery.

In Brief

The authors’ study provides long-term outcomes data on pediatric AVM patients treated with stereotactic radiosurgery. The study was derived from the largest multicenter observational cohort database, and it provides the best estimates of outcomes and complications in the pediatric population. The authors believe that these estimates will serve as important counseling information for patients and families.

Brain arteriovenous malformations (AVMs) are responsible for approximately 50% of all spontaneous intracranial hemorrhages occurring in the pediatric population (age < 18 years).19 The substantial cumulative risk of AVM hemorrhage over a child’s lifetime generally outweighs the risk of intervention, which generally favors an aggressive approach toward AVM management in the pediatric population.1,18 Stereotactic radiosurgery (SRS) is an effective intervention, either primarily or as a component of multimodality treatment, for pediatric AVMs, especially those not amenable to surgery or in patients who are unwilling or unable to undergo surgery.21,25 The limitations of existing pediatric AVM studies include single-center data, small sample size, heterogeneous patient populations that include adult patients, lack of time-dependent analysis, and failure to account for the competing risk of death. In order to better inform the long-term outcomes and risks of SRS for pediatric AVMs, we performed a multicenter, retrospective cohort analysis of individual patient data pooled from 8 member institutions of the International Radiosurgery Research Foundation (IRRF).

Methods

Patient Identification, Ethical Approval of Study, and Informed Consent

This study follows the guidelines set forth by the STROBE checklist. This study was approved by the IRB at each individual institution, and patient consent was waived by each IRB. We retrospectively reviewed a database of pediatric AVM patients (age < 18 years at the time of initial SRS) who underwent SRS at 8 institutions participating in the IRRF. Data on pediatric AVM patients from the previous comprehensive IRRF database (1987–2014) were updated retrospectively by each respective institution to include additional patients and follow-up data on outcomes and complications occurring up to and including 2018.6,7 Any pediatric AVM patients who were excluded in the previous database due to treatment with repeat SRS or inadequate follow-up were included in this updated database. The current database also included pediatric AVM patients who underwent SRS between 2014 and 2018, and data from additional participating institutions were included. Verification and attestation of data accuracy were performed by each respective institution. Individual patient data from each contributing institution were then de-identified and pooled by an independent third party.

Baseline Data and Variables

Baseline patient data included patient characteristics, AVM features, and SRS treatment parameters. Eloquent locations included the sensorimotor, language, and visual cortex, hypothalamus and thalamus, internal capsule, brainstem, cerebellar peduncles, and deep cerebellar nuclei.24 Deep locations included the thalamus, basal ganglia, and brainstem.28 The Spetzler-Martin (SM) grade, modified radiosurgery-based AVM score, and Virginia Radiosurgery AVM Scale score were calculated for each AVM.24,27,28

SRS was performed using the Gamma Knife, and the specific model used varied by year and availability at each institution. The SRS technique for AVMs has been previously described.30 In brief, the patient’s calvaria was affixed within a Leksell model G frame (Elekta AB) under anesthesia. The nidal angioarchitecture and spatial anatomy of the AVM were delineated on DSA and thin-slice (slice thickness 1–2 mm) contrast-enhanced MRI or on CTA when MRI was contraindicated.

Follow-Up and Outcomes

Neuroimaging follow-up, comprising MRI or CTA when MRI was contraindicated, was performed at 6-month intervals for the first 2 years after SRS and then annually thereafter. Patients with complete AVM obliteration on follow-up MRI were recommended to undergo confirmatory DSA. AVM obliteration was defined on MRI as a lack of abnormal flow voids or on DSA as an absence of anomalous arteriovenous shunting.

Radiation-induced changes (RICs) were radiologically defined as perinidal hyperintensities on T2-weighted or FLAIR MRI sequences. Symptomatic RICs were defined as RICs associated with any new or worsening neurological deterioration. Permanently symptomatic RICs were defined as symptomatic RICs without neurological recovery. Post-SRS hemorrhage was defined as any AVM-related intracranial hemorrhage during the latency period (time period between initial SRS treatment and AVM obliteration), regardless of associated neurological symptoms or lack thereof. Hemorrhages that occurred after AVM obliteration were also captured. SRS-associated cyst and tumor formation were also recorded.5 The composite endpoint of favorable outcome was defined as AVM obliteration without post-SRS hemorrhage or permanently symptomatic RICs. The follow-up period comprised clinical and neuroimaging follow-up, whichever was longer.

Statistical Analysis

All statistical analyses were performed using Stata (version 14.2; StataCorp). The follow-up duration was defined as the time interval from SRS to death or last follow-up. Rates of defined outcomes and complications, comprising favorable outcome, AVM obliteration, post-SRS hemorrhage, RICs (radiological, symptomatic, and permanent), cyst formation, and tumor formation, were reported as percentages. Incidences of post-SRS hemorrhage, cyst formation, and tumor formation were reported as number of new cases divided by the amount of patient-time at risk with 95% confidence intervals. To account for the competing risk of death and to avoid biased estimates of incidence, cumulative incidence and associated 95% CIs of AVM obliteration, post-SRS hemorrhage, cyst formation, and tumor formation were calculated using nonparametric cumulative incidence functions.2,8 Subgroup analyses were performed for pediatric AVM patients who underwent single-session SRS (i.e., no repeat SRS) and those who underwent single-session SRS as the only AVM treatment (i.e., no resection, embolization, or repeat SRS). Missing data were not imputed.

Results

Study Cohort Composition

The study cohort comprised 539 pediatric patients with brain AVMs. The contribution from each participating center included 193 patients from the University of Virginia, 173 patients from Taipei Veterans General Hospital, 135 patients from the University of Pittsburgh, 12 patients from the Cleveland Clinic, 9 patients from the Beaumont Health System, 8 patients from the University of Puerto Rico, 7 patients from New York University, and 2 patients from the University of Sherbrooke.

Table 1 details the patient, AVM, and SRS characteristics of the study cohort. The mean age of patients was 12.8 years, and 47.3% were female. Prior AVM hemorrhage occurred in 71.6%. Prior AVM interventions included external-beam radiation therapy (EBRT), resection, and embolization in 12.8%, 6.1%, and 16.9%, respectively. The mean AVM maximum diameter and nidus volume were 2.6 cm and 5.9 cm3, respectively. AVMs were localized to eloquent and deep brain areas in 75.9% and 34%, respectively. AVM-associated arterial aneurysms and deep venous drainage were present in 6.3% and 64%, respectively. The mean SRS margin dose was 20.2 Gy, and the median number of isocenters was 4. Repeat SRS was performed in 21.4% of the patients. The repeat SRS were performed for incomplete AVM obliteration after the initial SRS procedure. The number of patients who underwent 2, 3, 4, and 5 SRS procedures was 104, 7, 1, and 1, respectively. The mean follow-up duration after initial SRS was 85.8 months.

TABLE 1.

Patient, AVM, and SRS characteristics of the study cohort

CharacteristicOverall Cohort (n = 539)Single-Session SRS (n = 416)Single-Session SRS as Only Treatment (n = 305)
Age: mean; median (SD), yrs12.8; 13.3 (3.7)12.9; 13.4 (3.6)13; 13.7 (3.7)
Female, no. (%)255/539 (47.3)199/416 (47.8)142/305 (46.6)
Prior AVM hemorrhage, no. (%)386/539 (71.6)298/416 (71.6)220/305 (72.1)
Prior EBRT, no. (%)69/539 (12.8)31/416 (7.5)
Prior resection, no. (%)33/59 (6.1)24/416 (5.8)
Prior embolization, no. (%)91/539 (16.9)69/416 (16.6)
Max diameter: mean; median (SD), cm2.6; 2.3 (1.4)2.4; 2.2 (1.2)2.4; 2.2 (1.2)
Volume: mean; median (SD), cm35.9; 3 (10.2)5.2; 2.8 (9.1)5.1; 2.9 (6.9)
≥2 SRS treatments, no. (%)113/529 (21.4)
Max dose: mean; median (SD), Gy*36.7; 36 (7.3)36.8; 36 (7.1)36.4; 34 (7.3)
Margin dose: mean; median (SD), Gy*20.2; 20 (3.3)20.3; 20 (3.1)20.1; 19.5 (3.1)
Isodose, median (IQR), %*50 (50–58)50 (50–59)51.4 (50–58)
Isocenters, median (IQR), %*4 (2–9)4 (2–9)5 (2–10)
Eloquent location, no. (%)409/539 (75.9)308/416 (74)230/305 (75.4)
Deep location, no. (%)182/535 (34)132/413 (32)103/302 (34.1)
Aneurysm, no. (%)34/539 (6.3)28/416 (6.7)19/305 (6.2)
Deep venous drainage, no. (%)345/539 (64)256/416 (61.5)192/305 (63)
SM grade, no. (%)
 I49/539 (9.1)40/416 (9.6)30/305 (9.8)
 II164/539 (30.4)136/416 (32.7)91/305 (29.8)
 III243/539 (45.1)190/416 (45.7)145/305 (47.5)
 IV72/539 (13.4)45/416 (10.8)34/305 (11.2)
 V11/539 (2)5/416 (1.2)5/305 (1.6)
VRAS, no. (%)
 010/539 (1.9)8/416 (1.9)5/305 (1.6)
 175/539 (13.9)63/416 (15.1)37/305 (12.1)
 2183/539 (34)145/416 (34.9)115/305 (37.7)
 3157/539 (29.1)115/416 (27.6)81/305 (26.6)
 4114/539 (21.2)85/416 (20.4)67/305 (22)
RBAS: mean/median (SD)1.0/0.8 (1.0)0.9/0.8 (0.9)0.9/0.8 (0.7)
Follow-up: mean/median (SD, IQR), mos85.8/68.5 (66.6, 30.3–127.1)76.9/52.2 (65.7, 26.4–108.8)75.8/51.3 (65.2, 25.1–110.4)

RBAS = modified radiosurgery-based AVM score; VRAS = Virginia Radiosurgery AVM Scale; — = not applicable.

Initial SRS parameters.

Sensorimotor, language, and visual cortex; hypothalamus and thalamus; internal capsule; brainstem; cerebellar peduncles; and deep cerebellar nuclei.

Thalamus, basal ganglia, and brainstem.

Outcomes and Complications of the Overall Cohort

Table 2 details the outcomes and complications of the study cohort. A favorable outcome was achieved in 57% of the patients, and AVM obliteration was achieved in 64.3% of the patients. Of those in whom obliteration was achieved, 12.7% did not have confirmation by DSA. Of the entire cohort, 3.9% of the patients had obliteration demonstrated on MRI, but on DSA a residual nidus was present. The cumulative incidence of AVM obliteration after SRS was 63.6% (95% CI 58.8%–68.0%), 77.1% (95% CI 72.1%–81.3%), and 88.1% (95% CI 82.5%–92.0%) over 5, 10, and 15 years, respectively (Fig. 1A). Of the patients who underwent multiple SRS procedures, obliteration was achieved in 47.8% at the last follow-up. The incidence of post-SRS hemorrhage was 10.7 (95% CI 7.8–14.7) per 1000 patient-years. Hemorrhage after AVM obliteration occurred in 6 patients (1.7%; 5 confirmed by DSA, 1 determined by MRI only) at a median interval of 41.6 months (range 38.1–55.9 months) after obliteration. The cumulative incidence of post-SRS hemorrhage was 4.9% (95% CI 3.1%–7.2%), 9.7% (95% CI 6.4%–13.7%), and 14.5% (95% CI 9.5%–20.5%) over 5, 10, and 15 years, respectively (Fig. 1B).

TABLE 2.

Outcomes and complications

OutcomeOverall Cohort (n = 539)Single-Session SRS (n = 416)Single-Session SRS as Only Treatment (n = 305)
Favorable outcome307/539 (57)261/416 (62.7)202/305 (66.2)
AVM obliteration346/539 (64.3)285/415 (68.7)219/305 (71.8)
Post-SRS hemorrhage45/539 (8.4)21/416 (5.1)14/305 (4.6)
Radiological RIC202/526 (38.4)148/406 (36.5)120/297 (40.4)
 Symptomatic RIC55/536 (10.3)35/413 (8.5)22/303 (7.3)
 Permanently symptomatic RIC33/536 (6.2)22/413 (5.3)14/303 (4.6)
Delayed cyst11/529 (2.1)5/408 (1.2)4/301 (1.3)
 Symptomatic3/522 (0.6)0/403 (0)0/297 (0)
 Required intervention2/522 (0.4)0/403 (0)0/297 (0)
Tumor2/529 (0.4)1/408 (0.3)0/301 (0)

Values are presented as the number (%) of patients.

FIG. 1.
FIG. 1.

Cumulative incidence functions and associated 95% CIs for AVM obliteration (A), post-SRS hemorrhage (B), cyst formation (C), and tumor formation (D) after SRS for pediatric AVMs in the overall study cohort. Dashed vertical blue, purple, and yellow reference lines denote 5-, 10-, and 15-year time points after SRS, respectively. Figure is available in color online only.

The rates of radiological, symptomatic, and permanently symptomatic RIC were 38.4%, 10.3%, and 6.2%, respectively. Delayed cyst formation occurred in 2.1% at a median interval of 7.6 years after SRS. The incidence of cyst formation was 4.4 (95% CI 2.5–8.0) per 1000 patient-years. The cumulative incidence of cyst formation was 1.4% (95% CI 0.5%–3.1%), 5.5% (95% CI 2.3%–10.7%), and 6.9% (95% CI 3.1%–12.9%) over 5, 10, and 15 years, respectively (Fig. 1C). Tumor formation was observed in 2 patients (0.4%), and both lesions were benign meningiomas detected at 10 and 12 years after SRS. These were managed conservatively. The incidence of tumor formation was 0.8 (95% CI 0.2–3.2) per 1000 patient-years. The cumulative incidence of tumor formation was 3.1% (95% CI 0.6%–9.7%) over 15 years (Fig. 1D).

Subgroup Analysis of SM Grade I and II AVMs

Table 3 details the outcomes and complications of SM grade I and II AVMs. A favorable outcome was achieved in 64%. The cumulative incidence of AVM obliteration after SRS was 75.5% (95% CI 67.9%–81.5%), 85.3% (95% CI 77.9%–90.4%), and 95.5% (95% CI 80.2%–99.0%) over 5, 10, and 15 years, respectively. The cumulative incidence of post-SRS hemorrhage was 3.6% (95% CI 1.3%–7.9%), 5.5% (95% CI 2.0%–11.8%), and 12.0% (95% CI 4.2%–24.3%) over 5, 10, and 15 years, respectively. The cumulative incidence of cyst formation was 1.5% (95% CI 0.3%–5.0%), 5.3% (95% CI 0.8%–16.4%), and 5.3% (95% CI 0.8%–16.4%) over 5, 10, and 15 years, respectively. The cumulative incidence of tumor formation was 4.7% (95% CI 0.3%–19.6%) over 15 years.

TABLE 3.

Subgroup analysis of SM grade I and II AVMs

OutcomeSM Grade I & II AVMs (n = 213)
Favorable outcome136/213 (63.9)
AVM obliteration148/212 (69.8)
Post-SRS hemorrhage11/213 (5.2)
Radiological RICs70/209 (33.5)
 Symptomatic RICs15/212 (7.1)
 Permanently symptomatic RICs10/212 (4.7)
Delayed cyst3/211 (1.4)
 Symptomatic1/210 (0.5)
 Required intervention1/210 (0.5)
Tumor1/211 (0.5)

Values are presented as the number (%) of patients.

Outcomes and Complications of Single-Session SRS

Single-session SRS was performed to treat 416 pediatric AVMs (Table 1). The mean age of the patients in this subgroup was 12.9 years, and 47.3% were female. Prior AVM hemorrhage occurred in 71.6% of the patients. Prior AVM interventions included EBRT, resection, and embolization in 7.5%, 5.8%, and 16.6%, respectively. The mean AVM maximum diameter and nidus volume were 2.4 cm and 5.2 cm3, respectively. AVMs were localized to eloquent and deep brain areas in 74% and 32%, respectively. AVM-associated arterial aneurysms and deep venous drainage were present in 6.7% and 61.5%, respectively. The mean SRS margin dose was 20.3 Gy, and the median number of isocenters was 4. The mean follow-up duration was 76.9 months. A favorable outcome was achieved in 63% (Table 2). The cumulative incidence of AVM obliteration after SRS was 76.5% (95% CI 71.4%–80.8%), 83.8% (95% CI 78.6%–87.8%), and 91.7% (95% CI 85.9%–95.2%) over 5, 10, and 15 years, respectively (Fig. 2A). The incidence of post-SRS hemorrhage was 7.2 (95% CI 4.5–11.4) per 1000 patient-years. The cumulative incidence of post-SRS hemorrhage was 4.2% (95% CI 2.3%–6.8%), 5.3% (95% CI 2.8%–8.9%), and 7.1% (95% CI 3.4%–12.7%) over 5, 10, and 15 years, respectively (Fig. 2B).

FIG. 2.
FIG. 2.

Cumulative incidence functions and associated 95% CIs for AVM obliteration (A), post-SRS hemorrhage (B), cyst formation (C), and tumor formation (D) after SRS for pediatric AVMs in the single-session SRS subgroup. Dashed vertical blue, purple, and yellow reference lines denote 5-, 10-, and 15-year time points after SRS. Figure is available in color online only.

The rates of radiological, symptomatic, and permanently symptomatic RICs were 36.5%, 8.5%, and 5.3%, respectively. Delayed cyst formation occurred in 1.2% at a median interval of 3 years after SRS. The incidence of cyst formation was 3.1 (95% CI 1.3–7.4) per 1000 patient-years. The cumulative incidence of cyst formation was 1.3% (95% CI 0.3%–3.7%), 2.7% (95% CI 0.7%–7.2%), and 2.7% (95% CI 0.7%–7.2%) over 5, 10, and 15 years, respectively (Fig. 2C). The incidence of tumor formation was 0.6 (95% CI 0.09–4.4) per 1000 patient-years. The cumulative incidence of tumor formation was 2.3% (95% CI 0.2%–10.5%) over 15 years (Fig. 2D).

Outcomes and Complications of Single-Session SRS as the Only AVM Treatment

Single-session SRS was performed as the only AVM treatment modality in 305 patients (Table 1). The mean age of this subgroup was 13 years, and 46.6% were female. Prior AVM hemorrhage occurred in 72.1% of the patients. The mean AVM maximum diameter and nidus volume were 2.4 cm and 5.1 cm3, respectively. AVMs were localized to eloquent and deep brain areas in 75.4% and 34.1%, respectively. AVM-associated arterial aneurysms and deep venous drainage were present in 6.2% and 63%, respectively. The mean SRS margin dose was 20.1 Gy, and the median number of isocenters was 5. The mean follow-up duration was 75.8 months. A favorable outcome was achieved in 66% (Table 2). The cumulative incidence of AVM obliteration after SRS was 79.1% (95% CI 73.3%–83.7%), 87.7% (95% CI 81.8%–91.8%), and 93.5% (95% CI 87.3%–96.8%) over 5, 10, and 15 years, respectively (Fig. 3A). The incidence of post-SRS hemorrhage was 7.1 (95% CI 4.1–12.2) per 1000 patient-years. The cumulative incidence of post-SRS hemorrhage was 4.0% (95% CI 2.0%–7.1%), 4.0% (95% CI 2.0%–7.1%), and 6.6% (95% CI 2.5%–13.5%) over 5, 10, and 15 years, respectively (Fig. 3B).

FIG. 3.
FIG. 3.

Cumulative incidence functions and associated 95% CIs for AVM obliteration (A), post-SRS hemorrhage (B), and cyst formation (C) after SRS for pediatric AVMs in the single-session SRS as the only AVM treatment modality subgroup. Dashed vertical blue, purple, and yellow reference lines denote 5-, 10-, and 15-year time points after SRS. Figure is available in color online only.

The rates of radiological, symptomatic, and permanently symptomatic RICs were observed in 40.4%, 7.3%, and 4.6% of the patients, respectively. Delayed cyst formation occurred in 1.3% at a median interval of 2.5 years after SRS. The incidence of cyst formation was 3.5 (95% CI 1.3–9.3) per 1000 patient-years. The cumulative incidence of cyst formation was 1.9% (95% CI 0.5%–5.1%), 4.0% (95% CI 1.0%–10.7%), and 4.0% (95% CI 1.0%–10.7%) over 5, 10, and 15 years, respectively (Fig. 3C). No tumor formation was observed in this subgroup.

Discussion

In this multicenter study, we provided estimates of the long-term outcomes and risks of SRS for AVMs in the pediatric population. With a mean follow-up exceeding 7 years in a large cohort of pediatric AVM patients, favorable outcome was achieved in 57% of the overall population, which included those with previously treated AVMs and those who underwent repeat SRS. The higher rate of favorable outcome in the two subgroup analyses (63% for single-session SRS, 66% for single-session SRS as the only AVM treatment) may reflect selection bias and baseline differences rather than a true treatment effect of single-session, SRS-only therapy.21 However, prior nidal embolization has been shown to be a negative prognostic factor for post-SRS AVM obliteration, and repeat SRS may yield worse outcomes than initial SRS.10,21

Due to the risk of hemorrhage and its associated morbidity and mortality, complete nidal obliteration remains the primary goal of any AVM treatment. SRS is an effective treatment for pediatric AVMs, especially for those not amenable to surgery, with reported obliteration rates ranging from 60% to 80% at 4–5 years after SRS.9,11,13,14,17,23,25,31 In the current study comprising 539 pediatric AVM patients, obliteration was achieved in 64% after a mean follow-up of 86 months. To avoid upward bias of incidence estimates, as seen when using the Kaplan-Meier survival function, cumulative incidence functions adjusted for the competing risk of death were used in the estimations of cumulative obliteration, post-SRS hemorrhage, and rates of adverse radiation effects in the current study.2 As such, the cumulative obliteration rates of the overall cohort were 64%, 77%, and 88% over 5, 10, and 15 years, respectively.

Despite the long-term efficacy of SRS for AVMs, obliteration occurs in a delayed fashion, and patients remain at risk for AVM hemorrhage during the latency period between SRS and complete nidal occlusion. Therefore, as a safety assessment, post-SRS hemorrhage rates are often compared to the natural history of untreated AVMs.4,9,14,17,18,25 Post-SRS hemorrhage occurred in 8.4% of patients in the current study, resulting in an incidence of 10.7 hemorrhages per 1000 patient-years (annual post-SRS hemorrhage rate of 1.1%). After adjustment for the competing risk of death, the cumulative incidence of post-SRS hemorrhage was 4.9%, 9.7%, and 14.5% over 5, 10, and 15 years, respectively. Obliteration after SRS is often regarded as a definitive cure. However, AVM recurrence after an apparently curative intervention has been reported, and this phenomenon is more frequently observed in pediatric patients.20 We observed 6 cases of postobliteration hemorrhage (1.7%) at a median interval of 3.5 years after obliteration. Although these hemorrhages could be attributed to recurrent AVMs or angiographically occult micronidi, they could not be confirmed based on the available data.

RICs are the most frequently observed adverse radiation effect after SRS for AVMs. In a systematic review of 51 studies comprising 6779 AVMs treated with any SRS approach (i.e., single session, staged, or repeat), Ilyas et al. reported radiological, symptomatic, and permanently symptomatic RIC rates of 35.5%, 9.2%, and 3.8%, respectively.15 In the present study, RICs were radiologically evident in 38.4% of the overall cohort, including symptomatic and permanently symptomatic RICs in 10.3% and 6.2%, respectively. Although some overlap exists between patients in the systematic review and the current study, pediatric AVM patients appear to be slightly more susceptible to permanent RICs compared to pooled data from the literature.15

Due to the relative rarity of post-SRS cysts in AVM patients and the prolonged follow-up necessary for their detection, estimating the incidence of delayed cyst formation has been challenging. The small sample sizes of individual studies and case series dedicated to cyst formation have also hampered an accurate estimation of their cumulative incidence. In a systematic review of 22 studies comprising 2619 patients, Ilyas et al. reported an overall cyst formation rate of 3%, with a mean latency period of 6.5 years after any SRS approach. Among the cysts identified in the review, 32.8% were symptomatic and 32.8% required surgical intervention. In the current study, cyst formation was observed in 2.1% of the cases, and of these post-SRS cysts, 27.3% were symptomatic and 18.2% required intervention. The incidence of cyst formation was 4.4 cysts per 1000 patient-years, with cumulative rates of 1.4%, 5.5%, and 6.9% over 5, 10, and 15 years, respectively. The risk of post-SRS cyst formation in pediatric AVM patients seems to be slightly lower in comparison with pooled data from the literature.16

The risk of delayed tumor development after SRS is even more challenging to assess, and the extended interval between SRS and the development of secondary neoplasms may preclude an accurate estimation of risk. However, this risk may be of greater importance in children than in adults, given their relatively greater number of years at risk following SRS. In a previous study from the University of Virginia comprising 1309 AVM patients (pediatric and adult) treated with SRS, Starke et al. reported 3 cases of radiation-related neoplasms, including 2 meningiomas and 1 high-grade glioma, with cumulative incidences of 0%, 0.3%, and 2.6% at 3, 10, and 15 years, respectively.26 In a recent multicenter study assessing the risk of SRS-associated intracranial malignancy, the investigators observed no secondary intracranial malignancies among 1089 AVM patients (pediatric and adult) after a median follow-up of 8.1 years.29 Although there were no secondary intracranial malignancies in the current study, we found 2 cases (0.4%) of SRS-induced meningioma that were previously reported based on neuroimaging characteristics and behavior.22,26 Although no secondary intracranial malignancies were detected in the current study, SRS-associated malignant brain tumors have been reported in the literature.3 Since this risk appears to be higher than that found in the general population, longitudinal surveillance after SRS remains important.12

It is important to note the limitations of this retrospective study. The results are dependent on the accuracy and reliability of data from each participating center and, therefore, may be subject to reporting bias. Due to the nature of each contributing institution as a tertiary referral center for AVM SRS, detailed follow-up data, such as functional, seizure, and educational outcomes, could not be provided for every patient. Our database did not allow differentiation between delayed strokes and RICs. Therefore, we concede that a minority of patients with symptomatic post-SRS complications could have suffered from delayed infarcts rather than RICs. Additionally, the effects of post-SRS hemorrhage on neurological or functional outcomes were not captured. Despite the large sample size and long follow-up duration of the current study, our analyses may still be insufficient for the detection of rare and very delayed SRS-associated complications, such as cyst and tumor formation. Due to the low incidences of cyst and tumor formation, we were unable to identify their respective risk factors. Furthermore, AVM recurrence after angiographically confirmed obliteration, which has been reported predominantly in pediatric patients, was not documented in this study. AVM treatments subsequent to post-SRS hemorrhage were not recorded.

Differences in outcomes and complications between the overall cohort and subgroup analyses may reflect selection biases and differences in baseline characteristics, and therefore, they should not be interpreted as an effect of a particular treatment approach. No direct comparisons against the natural history of pediatric AVMs could be made, as control (untreated) cohort data were not available. Furthermore, it is important to note that SRS is often reserved for AVMs with high surgical risks (i.e., SM grade III–V AVMs) or for patients who refuse craniotomy (i.e., SM grade I and II AVMs). However, this study was also not designed to compare the outcomes of SRS to those of resection for pediatric AVMs. Treatment algorithms for pediatric AVMs are subject to considerable variability, as they are biased by the expertise, experience, and preferences of the participating institutions and responsible physicians. The findings of the current study were limited to the pediatric population, and as such, they should not be generalized to the adult population. Since SM grade II and III AVMs comprised the majority of the study cohort, our results may not be generalizable to pediatric patients with high-grade (i.e., SM grade VI and V) AVMs. The majority of patients were treated at one of the 3 major SRS centers participating in the IRRF, and thus, the reported outcomes may not be generalizable to less experienced centers or to centers employing different techniques.

Conclusions

Complete obliteration can be expected in 60%–80% of pediatric AVMs treated with SRS over 5 years of follow-up. The annual post-SRS hemorrhage risk for pediatric AVMs is approximately 1%, which compares favorably with the natural history. Although nearly 40% of SRS-treated pediatric AVM patients will develop neuroimaging evidence of RICs, less than one-third of these cases have neurological manifestations. The cumulative rates of cyst and benign tumor formation were estimated to be 7% and 3% over 15 years, respectively. Although SRS-related malignancies were not detected in the pediatric AVM population, longitudinal surveillance in these patients remains prudent.

Disclosures

Dr. Grills reports less than 5% stock ownership in Greater Michigan Gamma Knife, where she also serves on the executive board of directors. Dr. Lunsford reports stock ownership in Elekta AB; he is a consultant for Insightec and DSMB. Dr. Kondziolka reports funding from Brainlab for research support in brain tumor imaging (not related to this study).

Author Contributions

Conception and design: Sheehan, Chen. Acquisition of data: Lee, Kano, Kearns, Tzeng, Atik, Joshi, Huang, Mathieu, Iorio-Morin, Quinn, Siddiqui, Marvin, Feliciano, Faramand. Analysis and interpretation of data: Sheehan, Chen, Ding. Drafting the article: Chen, Ding. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Statistical analysis: Chen. Administrative/technical/material support: Sheehan. Study supervision: Sheehan.

Supplemental Information

Previous Presentations

The contents of this study were orally presented at the 67th Annual Meeting of the Congress of Neurological Surgeons, October 19–23, 2019, San Francisco, California.

References

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    Austin PC, Lee DS, Fine JP: Introduction to the analysis of survival data in the presence of competing risks. Circulation 133:601609, 2016

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    Berman EL, Eade TN, Brown D, Weaver M, Glass J, Zorman G, et al.: Radiation-induced tumor after stereotactic radiosurgery for an arteriovenous malformation: case report. Neurosurgery 61:E1099, 2007

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  • 4

    Brown RD Jr, Wiebers DO, Forbes G, O’Fallon WM, Piepgras DG, Marsh WR, et al.: The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg 68:352357, 1988

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    Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL: Sarcoma arising in irradiated bone: report of eleven cases. 1948. Cancer 82:834, 1998

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  • 6

    Chen CJ, Ding D, Kano H, Mathieu D, Kondziolka D, Feliciano C, et al.: Stereotactic radiosurgery for pediatric versus adult brain arteriovenous malformations. Stroke 49:19391945, 2018

    • Search Google Scholar
    • Export Citation
  • 7

    Chen CJ, Lee CC, Ding D, Tzeng SW, Kearns KN, Kano H, et al.: Stereotactic radiosurgery for unruptured versus ruptured pediatric brain arteriovenous malformations. Stroke 50:27452751, 2019

    • Search Google Scholar
    • Export Citation
  • 8

    Coviello E: STCOMPET: Stata module to generate cumulative incidence in presence of competing events. Statistical Software Components. Boston: Boston College Department of Economics, 2003 (https://ideas.repec.org/c/boc/bocode/s431301.html) [Accessed January 2, 2020]

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    Dinca EB, de Lacy P, Yianni J, Rowe J, Radatz MW, Preotiuc-Pietro D, et al.: Gamma knife surgery for pediatric arteriovenous malformations: a 25-year retrospective study. J Neurosurg Pediatr 10:445450, 2012

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  • 10

    Ding D, Xu Z, Shih HH, Starke RM, Yen CP, Cohen-Inbar O, et al.: Worse outcomes after repeat vs initial stereotactic radiosurgery for cerebral arteriovenous malformations: a retrospective matched-cohort study. Neurosurgery 79:690700, 2016

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    • Export Citation
  • 11

    Ding D, Xu Z, Yen CP, Starke RM, Sheehan JP: Radiosurgery for unruptured cerebral arteriovenous malformations in pediatric patients. Acta Neurochir (Wien) 157:281291, 2015

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  • 12

    Dolecek TA, Propp JM, Stroup NE, Kruchko C: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol 14 (Suppl 5):v1v49, 2012

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  • 13

    Galván De la Cruz OO, Ballesteros-Zebadúa P, Moreno-Jiménez S, Celis MA, García-Garduño OA: Stereotactic radiosurgery for pediatric patients with intracranial arteriovenous malformations: variables that may affect obliteration time and probability. Clin Neurol Neurosurg 129:6266, 2015

    • Search Google Scholar
    • Export Citation
  • 14

    Hanakita S, Koga T, Shin M, Igaki H, Saito N: The long-term outcomes of radiosurgery for arteriovenous malformations in pediatric and adolescent populations. J Neurosurg Pediatr 16:222231, 2015

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    Ilyas A, Chen CJ, Ding D, Buell TJ, Raper DMS, Lee CC, et al.: Radiation-induced changes after stereotactic radiosurgery for brain arteriovenous malformations: a systematic review and meta-analysis. Neurosurgery 83:365376, 2018

    • Search Google Scholar
    • Export Citation
  • 16

    Ilyas A, Chen CJ, Ding D, Mastorakos P, Taylor DG, Pomeraniec IJ, et al.: Cyst formation after stereotactic radiosurgery for brain arteriovenous malformations: a systematic review. J Neurosurg 128:13541363, 2018

    • Search Google Scholar
    • Export Citation
  • 17

    Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Awan NR, et al.: Stereotactic radiosurgery for arteriovenous malformations, part 2: management of pediatric patients. J Neurosurg Pediatr 9:110, 2012

    • Search Google Scholar
    • Export Citation
  • 18

    Kim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL: Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology 83:590597, 2014

    • Search Google Scholar
    • Export Citation
  • 19

    Meyer-Heim AD, Boltshauser E: Spontaneous intracranial haemorrhage in children: aetiology, presentation and outcome. Brain Dev 25:416421, 2003

    • Search Google Scholar
    • Export Citation
  • 20

    Morgan MK, Patel NJ, Simons M, Ritson EA, Heller GZ: Influence of the combination of patient age and deep venous drainage on brain arteriovenous malformation recurrence after surgery. J Neurosurg 117:934941, 2012

    • Search Google Scholar
    • Export Citation
  • 21

    Russell D, Peck T, Ding D, Chen CJ, Taylor DG, Starke RM, et al.: Stereotactic radiosurgery alone or combined with embolization for brain arteriovenous malformations: a systematic review and meta-analysis. J Neurosurg 128:13381348, 2018

    • Search Google Scholar
    • Export Citation
  • 22

    Sheehan J, Yen CP, Steiner L: Gamma knife surgery-induced meningioma. Report of two cases and review of the literature. J Neurosurg 105:325329, 2006

    • Search Google Scholar
    • Export Citation
  • 23

    Sheth SA, Potts MB, Sneed PK, Young WL, Cooke DL, Gupta N, et al.: Angiographic features help predict outcome after stereotactic radiosurgery for the treatment of pediatric arteriovenous malformations. Childs Nerv Syst 30:241247, 2014

    • Search Google Scholar
    • Export Citation
  • 24

    Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:476483, 1986

  • 25

    Starke RM, Ding D, Kano H, Mathieu D, Huang PP, Feliciano C, et al.: International multicenter cohort study of pediatric brain arteriovenous malformations. Part 2: Outcomes after stereotactic radiosurgery. J Neurosurg Pediatr 19:136148, 2017

    • Search Google Scholar
    • Export Citation
  • 26

    Starke RM, Yen CP, Chen CJ, Ding D, Mohila CA, Jensen ME, et al.: An updated assessment of the risk of radiation-induced neoplasia after radiosurgery of arteriovenous malformations. World Neurosurg 82:395401, 2014

    • Search Google Scholar
    • Export Citation
  • 27

    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 119:981987, 2013

    • Search Google Scholar
    • Export Citation
  • 28

    Wegner RE, Oysul K, Pollock BE, Sirin S, Kondziolka D, Niranjan A, et al.: A modified radiosurgery-based arteriovenous malformation grading scale and its correlation with outcomes. Int J Radiat Oncol Biol Phys 79:11471150, 2011

    • Search Google Scholar
    • Export Citation
  • 29

    Wolf A, Naylor K, Tam M, Habibi A, Novotny J, Liščák R, et al.: Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study. Lancet Oncol 20:159164, 2019

    • Search Google Scholar
    • Export Citation
  • 30

    Yamamoto M, Jimbo M, Ide M, Tanaka N, Lindquist C, Steiner L: Long-term follow-up of radiosurgically treated arteriovenous malformations in children: report of nine cases. Surg Neurol 38:95100, 1992

    • Search Google Scholar
    • Export Citation
  • 31

    Zeiler FA, Janik MK, McDonald PJ, Kaufmann AM, Fewer D, Butler J, et al.: Gamma Knife radiosurgery for pediatric arteriovenous malformations: a Canadian experience. Can J Neurol Sci 43:8286, 2016

    • Search Google Scholar
    • Export Citation

Illustration from Warsi et al. (pp 540–547). Copyright Nebras Warsi. Published with permission.

  • View in gallery

    Cumulative incidence functions and associated 95% CIs for AVM obliteration (A), post-SRS hemorrhage (B), cyst formation (C), and tumor formation (D) after SRS for pediatric AVMs in the overall study cohort. Dashed vertical blue, purple, and yellow reference lines denote 5-, 10-, and 15-year time points after SRS, respectively. Figure is available in color online only.

  • View in gallery

    Cumulative incidence functions and associated 95% CIs for AVM obliteration (A), post-SRS hemorrhage (B), cyst formation (C), and tumor formation (D) after SRS for pediatric AVMs in the single-session SRS subgroup. Dashed vertical blue, purple, and yellow reference lines denote 5-, 10-, and 15-year time points after SRS. Figure is available in color online only.

  • View in gallery

    Cumulative incidence functions and associated 95% CIs for AVM obliteration (A), post-SRS hemorrhage (B), and cyst formation (C) after SRS for pediatric AVMs in the single-session SRS as the only AVM treatment modality subgroup. Dashed vertical blue, purple, and yellow reference lines denote 5-, 10-, and 15-year time points after SRS. Figure is available in color online only.

  • 1

    ApSimon HT, Reef H, Phadke RV, Popovic EA: A population-based study of brain arteriovenous malformation: long-term treatment outcomes. Stroke 33:27942800, 2002

    • Search Google Scholar
    • Export Citation
  • 2

    Austin PC, Lee DS, Fine JP: Introduction to the analysis of survival data in the presence of competing risks. Circulation 133:601609, 2016

    • Search Google Scholar
    • Export Citation
  • 3

    Berman EL, Eade TN, Brown D, Weaver M, Glass J, Zorman G, et al.: Radiation-induced tumor after stereotactic radiosurgery for an arteriovenous malformation: case report. Neurosurgery 61:E1099, 2007

    • Search Google Scholar
    • Export Citation
  • 4

    Brown RD Jr, Wiebers DO, Forbes G, O’Fallon WM, Piepgras DG, Marsh WR, et al.: The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg 68:352357, 1988

    • Search Google Scholar
    • Export Citation
  • 5

    Cahan WG, Woodard HQ, Higinbotham NL, Stewart FW, Coley BL: Sarcoma arising in irradiated bone: report of eleven cases. 1948. Cancer 82:834, 1998

    • Search Google Scholar
    • Export Citation
  • 6

    Chen CJ, Ding D, Kano H, Mathieu D, Kondziolka D, Feliciano C, et al.: Stereotactic radiosurgery for pediatric versus adult brain arteriovenous malformations. Stroke 49:19391945, 2018

    • Search Google Scholar
    • Export Citation
  • 7

    Chen CJ, Lee CC, Ding D, Tzeng SW, Kearns KN, Kano H, et al.: Stereotactic radiosurgery for unruptured versus ruptured pediatric brain arteriovenous malformations. Stroke 50:27452751, 2019

    • Search Google Scholar
    • Export Citation
  • 8

    Coviello E: STCOMPET: Stata module to generate cumulative incidence in presence of competing events. Statistical Software Components. Boston: Boston College Department of Economics, 2003 (https://ideas.repec.org/c/boc/bocode/s431301.html) [Accessed January 2, 2020]

    • Search Google Scholar
    • Export Citation
  • 9

    Dinca EB, de Lacy P, Yianni J, Rowe J, Radatz MW, Preotiuc-Pietro D, et al.: Gamma knife surgery for pediatric arteriovenous malformations: a 25-year retrospective study. J Neurosurg Pediatr 10:445450, 2012

    • Search Google Scholar
    • Export Citation
  • 10

    Ding D, Xu Z, Shih HH, Starke RM, Yen CP, Cohen-Inbar O, et al.: Worse outcomes after repeat vs initial stereotactic radiosurgery for cerebral arteriovenous malformations: a retrospective matched-cohort study. Neurosurgery 79:690700, 2016

    • Search Google Scholar
    • Export Citation
  • 11

    Ding D, Xu Z, Yen CP, Starke RM, Sheehan JP: Radiosurgery for unruptured cerebral arteriovenous malformations in pediatric patients. Acta Neurochir (Wien) 157:281291, 2015

    • Search Google Scholar
    • Export Citation
  • 12

    Dolecek TA, Propp JM, Stroup NE, Kruchko C: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol 14 (Suppl 5):v1v49, 2012

    • Search Google Scholar
    • Export Citation
  • 13

    Galván De la Cruz OO, Ballesteros-Zebadúa P, Moreno-Jiménez S, Celis MA, García-Garduño OA: Stereotactic radiosurgery for pediatric patients with intracranial arteriovenous malformations: variables that may affect obliteration time and probability. Clin Neurol Neurosurg 129:6266, 2015

    • Search Google Scholar
    • Export Citation
  • 14

    Hanakita S, Koga T, Shin M, Igaki H, Saito N: The long-term outcomes of radiosurgery for arteriovenous malformations in pediatric and adolescent populations. J Neurosurg Pediatr 16:222231, 2015

    • Search Google Scholar
    • Export Citation
  • 15

    Ilyas A, Chen CJ, Ding D, Buell TJ, Raper DMS, Lee CC, et al.: Radiation-induced changes after stereotactic radiosurgery for brain arteriovenous malformations: a systematic review and meta-analysis. Neurosurgery 83:365376, 2018

    • Search Google Scholar
    • Export Citation
  • 16

    Ilyas A, Chen CJ, Ding D, Mastorakos P, Taylor DG, Pomeraniec IJ, et al.: Cyst formation after stereotactic radiosurgery for brain arteriovenous malformations: a systematic review. J Neurosurg 128:13541363, 2018

    • Search Google Scholar
    • Export Citation
  • 17

    Kano H, Kondziolka D, Flickinger JC, Yang HC, Flannery TJ, Awan NR, et al.: Stereotactic radiosurgery for arteriovenous malformations, part 2: management of pediatric patients. J Neurosurg Pediatr 9:110, 2012

    • Search Google Scholar
    • Export Citation
  • 18

    Kim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL: Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology 83:590597, 2014

    • Search Google Scholar
    • Export Citation
  • 19

    Meyer-Heim AD, Boltshauser E: Spontaneous intracranial haemorrhage in children: aetiology, presentation and outcome. Brain Dev 25:416421, 2003

    • Search Google Scholar
    • Export Citation
  • 20

    Morgan MK, Patel NJ, Simons M, Ritson EA, Heller GZ: Influence of the combination of patient age and deep venous drainage on brain arteriovenous malformation recurrence after surgery. J Neurosurg 117:934941, 2012

    • Search Google Scholar
    • Export Citation
  • 21

    Russell D, Peck T, Ding D, Chen CJ, Taylor DG, Starke RM, et al.: Stereotactic radiosurgery alone or combined with embolization for brain arteriovenous malformations: a systematic review and meta-analysis. J Neurosurg 128:13381348, 2018

    • Search Google Scholar
    • Export Citation
  • 22

    Sheehan J, Yen CP, Steiner L: Gamma knife surgery-induced meningioma. Report of two cases and review of the literature. J Neurosurg 105:325329, 2006

    • Search Google Scholar
    • Export Citation
  • 23

    Sheth SA, Potts MB, Sneed PK, Young WL, Cooke DL, Gupta N, et al.: Angiographic features help predict outcome after stereotactic radiosurgery for the treatment of pediatric arteriovenous malformations. Childs Nerv Syst 30:241247, 2014

    • Search Google Scholar
    • Export Citation
  • 24

    Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:476483, 1986

  • 25

    Starke RM, Ding D, Kano H, Mathieu D, Huang PP, Feliciano C, et al.: International multicenter cohort study of pediatric brain arteriovenous malformations. Part 2: Outcomes after stereotactic radiosurgery. J Neurosurg Pediatr 19:136148, 2017

    • Search Google Scholar
    • Export Citation
  • 26

    Starke RM, Yen CP, Chen CJ, Ding D, Mohila CA, Jensen ME, et al.: An updated assessment of the risk of radiation-induced neoplasia after radiosurgery of arteriovenous malformations. World Neurosurg 82:395401, 2014

    • Search Google Scholar
    • Export Citation
  • 27

    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 119:981987, 2013

    • Search Google Scholar
    • Export Citation
  • 28

    Wegner RE, Oysul K, Pollock BE, Sirin S, Kondziolka D, Niranjan A, et al.: A modified radiosurgery-based arteriovenous malformation grading scale and its correlation with outcomes. Int J Radiat Oncol Biol Phys 79:11471150, 2011

    • Search Google Scholar
    • Export Citation
  • 29

    Wolf A, Naylor K, Tam M, Habibi A, Novotny J, Liščák R, et al.: Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study. Lancet Oncol 20:159164, 2019

    • Search Google Scholar
    • Export Citation
  • 30

    Yamamoto M, Jimbo M, Ide M, Tanaka N, Lindquist C, Steiner L: Long-term follow-up of radiosurgically treated arteriovenous malformations in children: report of nine cases. Surg Neurol 38:95100, 1992

    • Search Google Scholar
    • Export Citation
  • 31

    Zeiler FA, Janik MK, McDonald PJ, Kaufmann AM, Fewer D, Butler J, et al.: Gamma Knife radiosurgery for pediatric arteriovenous malformations: a Canadian experience. Can J Neurol Sci 43:8286, 2016

    • Search Google Scholar
    • Export Citation

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