radiosurgery for large cerebral arteriovenous malformations

CLINICAL ARTICLE

Radiosurgery for large cerebralarteriovenous malformations

Seung-Yeob Yang & Dong Gyu Kim & Hyun-Tai Chung &

Sun Ha Paek & Jae Hyo Park & Dae Hee Han

Received: 1 May 2007 /Accepted: 22 February 2008 /Published online: 10 February 2009# Springer-Verlag 2008

AbstractBackground Radiosurgery is an effective treatment optionfor patients with small to medium sized arteriovenousmalformations. However, it is not generally accepted as aneffective tool for larger (>14 cm3) arteriovenous malforma-tions because of low obliteration rates. The authors assessedthe applicability and effectiveness of radiosurgery for largearteriovenous malformations.Method We performed a retrospective study of 46 consec-utive patients with more than 14 ml of arteriovenousmalformations who were treated with radiosurgery using alinear accelerator and gamma knife (GK). They weregrouped according to their initial clinical presentation—17presented with and 29 without haemorrhage. To assess theeffect of embolization, these 46 patients were also regroupedinto two subgroups—25 with and 21 without preradiosur-gical embolization. Arteriovenous malformations found tohave been incompletely obliterated after 3-year follow-upneuroimaging studies were re-treated using a GK.

Findings The mean treatment volume was 29.5 ml (range,14.0–65.0) and the mean marginal dose was 14.1 Gy(range, 10.0–20.0). The mean clinical follow-up periodsafter initial radiosurgery was 78.1 months (range, 34.0–166.4). Depending on the results of the angiography, 11 of33 patients after the first radiosurgery and three of fourpatients after the second radiosurgery showed completeobliteration. Twenty patients received the second radio-surgery and their mean volume was significantly smallerthan their initial volume (P=0.017). The annual haemor-rhage rate after radiosurgery was 2.9% in the haemorrhagegroup (mean follow-up 73.3 months) and 3.1% in thenonhaemorrhage group (mean follow-up 66.5 months) (P=0.941). Preradiosurgical embolization increased the risk ofhaemorrhage for the nonhaemorrhage group (HR, 28.03;95% CI, 1.08–6,759.64; P=0.039), whereas it had no effecton the haemorrhage group. Latency period haemorrhageoccurred in eight patients in the embolization group, but inno patient in the nonembolization group (P=0.004).Conclusions Radiosurgery may be a safe and effectivearteriovenous malformation treatment method that is worthconsidering as an alternative treatment option for a largearteriovenous malformation.

Keywords Arteriovenous malformation . Embolization .

Haemorrhage . Obliteration . Radiosurgery

Introduction

Large arteriovenous malformations are difficult to treat,despite adequately applied multimodal treatments [11, 23],and have higher morbidity and mortality rates than smallerarteriovenous malformations. Although radiosurgery sig-nificantly decreases the risk of haemorrhage in patients

Acta Neurochir (2009) 151:113–124DOI 10.1007/s00701-008-0173-5

S.-Y. YangDepartment of Neurosurgery,Dongguk University College of Medicine,Goyang, Gyeonggi-do, South Korea

D. G. Kim (*) :H.-T. Chung : S. H. Paek :D. H. HanDepartment of Neurosurgery,Seoul National University College of Medicine,28 Yeongon-dong, Jongno-gu,Seoul 110-744, South Koreae-mail: [email protected]

J. H. ParkDepartment of Neurosurgery,Kangwon National University College of Medicine,Chuncheon, Kangwon-do, South Korea

with arteriovenous malformation [21] even before there isangiographic evidence of obliteration, it plays a limitedrole in the management of large arteriovenous malforma-tions. It is generally accepted that the complication rateafter radiosurgery for large arteriovenous malformations isunacceptably high when sufficient dose (22–25 Gy) isapplied to occlude the nidus [16, 24, 25]. Therefore, untilnow, radiosurgery has often been recommended as one ofthe multimodal therapies for large arteriovenous malfor-mations in combination with endovascular embolization ormicrosurgical excision, or both [9, 23].

Unfortunately, new neurological deficits occur in about4–40% of patients who have undergone arteriovenousmalformation embolization [9, 23], and recanalization hasbeen reported to occur in approximately 15% of patientsafter embolization [9, 31]. The recognition of these thera-peutic limitations led our group to treat the patients with alarge arteriovenous malformation using suboptimal-dose(10–20 Gy) radiosurgery. However, the role of suboptimal-dose radiosurgery for large arteriovenous malformation hasnot been well understood. The objective of this study was toassess whether suboptimal-dose radiosurgery is a safe andeffective treatment method for large arteriovenous malfor-mations based on initial clinical presentations.

Materials and methods

Patients

Between March 1993 and September 2003, 46 patients whohad an arteriovenous malformation more than 14 ml involume underwent suboptimal-dose radiosurgery. These 46patients participated in the present study. The patients’baseline characteristics at the time of initial radiosurgeryare summarized in Table 1. The patients were treated toobliterate their arteriovenous malformation completely orpartially by endovascular embolization before January 2000.After then, however, no patient underwent an endovascularembolization procedure to reduce the arteriovenous malfor-mation size. In principle, our aim for endovascular emboli-zation was not to reduce the size, but to reduce the risk ofbleeding. Preradiosurgical embolization was performed incase of angioarchitectural abnormalities believed to increasethe risk of haemorrhage. Namely, flow-related aneurysms,intranidal aneurysms, and venous aneurysms were treatedusing embolization before radiosurgery. As an initialtreatment before radiosurgery, 25 patients had undergone32 sessions of endovascular embolization; they were allreferred to our hospital for the purpose of radiosurgery fora residual arteriovenous malformation. Embolization wasperformed in all cases with n-butyl cyanoacrylate (Histoacryl;Braun, Melsungen, Germany). Among the 46 patients, five

were found to have at least one aneurysm. Intranidalaneurysms were identified in three of these five patients, aflow-related aneurysm in another, and a flow-unrelated 2 mmsized aneurysm in the fifth [33]. Endovascular coil emboli-zation was performed in four of these five patients, andobservation only for the remaining patient, who had a 2 mmsized tiny aneurysm unrelated to flow.

The patients were carefully selected for radiosurgery bycerebrovascular neurosurgeons, experts in radiosurgery, andcerebrovascular neurologists. Also, radiosurgery was rec-ommended for those who were considered at high risk ofmicrosurgical related morbidities or mortality associatedwith direct surgery under general anesthesia (≥class 4 of the

Table 1 Baseline characteristics and initial presentation

Hemorrhagegroup

Nonhemorrhagegroup

(n=17) (n=29)

DemographyMean (SD) age in years 29.2 (10.9) 34.1 (14.0)Male/female 17/12 10/7Median initial KPS (range) 100 (80–100) 80 (50–100)Clinical featuresPreradiosurgical embolization 13 (76.4) 12 (41.4)Hematoma removal beforeradiosurgery

3 0

Intracerebral aneurysm 2 3Initial presentationHemorrhage 17 0Seizure 0 16Chronic headache 0 7Focal neurological deficit 0 2Incidental found 0 4Details of AVMMean (SD) AVM volume (ml) 30.2 (12.8) 29.1 (13.0)AVM diameter3–6 cm 12 20>6 cm 5 9Eloquent brain locationa 15 (88) 24 (83)Deep venous drainagea 10 (59) 17 (58)Spetzler–Martin grade [37]I, II 0 0III 2 4IV 10 17V 5 8

Radiosurgical dosimetryLinear accelerator radiosurgery 6 5Mean (SD) marginal dose 16.1 (2.8) 14.2 (1.2)Gamma knife radiosurgery 11 24Mean (SD) marginal dose 13.8 (1.9) 13.9 (2.3)

Data are numbers (%) of patients unless otherwise specifiedAVM arteriovenous malformation, KPS Karnofsky performance scale,SD standard deviationa Eloquent brain location and deep venous drainage according to thecriteria of Spetzler and Martin [37]

114 S.-Y. Yang et al.

American Society of Anesthesiologists physical statusclassification system). We primarily recommended that allpatients be considered as good candidates for resection,such as those harboring Spetzler–Martin Grade [37] I, II orIII lesions, as resection is the most rational treatment;however, the patients included in this study eventuallychose radiosurgery.

The institutional review board of our hospital approvedthis study. However, it did not require informed consentfrom these patients for their inclusion in this study becausethe study depended only on information obtained as apart of the patients’ routine clinical care and their medicalrecords.

Radiosurgical technique

Radiosurgery was performed in patients under localanesthesia, which was supplemented with intravenoussedation. Between March 1993 and November 1997, 11patients were treated using a linear accelerator (LINAC).For LINAC-based treatment, we used a commercial stereo-tactic frame (Fisher Scientific, Schwerte, Germany) and aour own radiosurgery system (Green Knife System, Seoul,Republic of Korea) that consists of planning software, anon-invasive immobilization device, tertiary collimators, acollimator adaptor, and quality assurance devices. A6 MV X-ray beam produced by a LINAC (CLINAC2100C, Varian, Palo Alto, CA) was used. From December1997, patients were treated using a GK B or C-modelwith Leksell Gamma Plan (Elekta, Stockholm, Sweden).Radiosurgery was guided by angiography and computedtomography (CT) until November 1997; thereafter, it wasguided by angiography and MRI. Image-integrated treat-ment planning was performed jointly by neurosurgeonsand interventional neuroradiologists with the aid of theLeksell Gamma Plan or the Green Knife System. All patientswith a large arteriovenous malformation were treated usingsuboptimal-dose (10–20 Gy) radiosurgery. Suboptimal-dose radiosurgery is a simple method in which the entirearteriovenous malformation nidus is included at initialradiosurgery and the radiation dose is reduced to protectthe surrounding brain tissue despite the expectation of alow obliteration rate. In other words, suboptimal-doseradiosurgery for large arteriovenous malformation onlymeans radiosurgery using less than optimal range treatmentdoses because large treatment volumes necessitated the useof lower doses to reduce the risk of radiation-inducedcomplications. Kondziolka et al. [16] determined that thebest results were achieved when optimal doses between 22and 25 Gy were delivered at the periphery of the lesion.Several authors [7, 8, 13, 40] reported that the treatmentfailure was clearly associated with low treatment doses(particularly lower than or equal to 15 Gy). Nevertheless,

radiation doses were determined, and about 10–15% lessthan the 1% complication line of Kjellberg et al. forarteriovenous malformation [15] was planned for thearteriovenous malformation margin. Three years later, theradiosurgical outcome was confirmed using angiographyand thereafter any reduced remnant arteriovenous malfor-mations were repeatedly treated using GK. Dose selectionfor retreatment was based primarily on target volume, priorradiosurgery, patient status, and location. The dosesprescribed were lower than those generally used for primaryarteriovenous malformation radiosurgery.

Follow-up evaluations

Patients were clinically evaluated every 3 months afterradiosurgery. A MRI or CT was performed every 6 months.Angiography was recommended at 3 years after radiosurgery,but was performed earlier in patients whose arteriovenousmalformation had disappeared on CT or MRI. Disappearanceof the arteriovenous malformation was defined as thedisappearance of enhancement of the nidus and drainingvessels on CTor the absence of flow-void signal abnormalitieson MRI. However, the cure, which was regarded as treatmentend point, was defined as angiographic obliteration of anarteriovenous malformation. If the MRI obtained at 3 yearsdid not showed disappearance of arteriovenous malformation,follow-up angiography was generally performed. And then,the second radiosurgical treatment was simultaneouslyrecommended if angiography did not demonstrate arterio-venous malformation obliteration. On average the time tocure, if cure occurs, is 2 years from initial treatment.Although lower marginal doses may lead to late cures,these are unlikely after 4 years from treatment [17]. Thefollow-up protocol and definition of outcome used forrepeated treatments were the same as those for primaryarteriovenous malformation radiosurgery. The determinationof arteriovenous malformation obliteration on imagingstudies was independently assessed by both neuroradiolo-gists and neurosurgeons.

Treatment failure was defined as: (1) retreatment withsurgery or (2) radiosurgical related mortality. Clinical follow-up was continued even after obliteration of the arteriovenousmalformation in the majority of patients. Radiosurgicalrelated complications were defined as: (1) postradiosurgicalimaging abnormalities, (2) radiosurgical induced clinicalsymptoms and signs, (3) radiosurgical induced complica-tions requiring steroid treatment or surgical intervention,and (4) treatment-related deaths. Postradiosurgical imagingabnormalities were defined on MRI as: (1) hyperintensesignals on T2-weighted images in surrounding normal braintissue unrelated to prior surgery, haemorrhage, or previouslyidentified encephalomalacic areas [14]; (2) radiation necrosisdetected as hyperintense signals in the arteriovenous malfor-

Radiosurgery for arteriovenous malformations 115

mation region on contrast-enhanced T1-weighted imagescompared with the nonenhanced sequences; and (3) delayedcyst formation that was not induced by collections of fluidoccupying a cavity remaining from a resolved hematoma orby brain tissue loss due to encephalomalacia followingresection, but rather directly induced by radiosurgery. Toensure a consistent classification of radiation effects through-out this analysis, two neurosurgeons and one neuroradiolo-gist in our center reviewed all available pretreatment andfollow-up imaging studies without the patients’ information.Wherever different opinions were encountered, the caseswere reexamined simultaneously and the results wererecorded after a consensus agreement had been reached.Any possible intraobserver bias in the categorizing processwas thereby minimized.

Information about all patients was recorded on a radio-surgical database at the time of their treatment and at eachclinical follow-up visit. Initial arteriovenous malformationvolumes were measured using angiography in combinationwith either CT or MRI, and the final follow-up volumeswere measured using MRI with or without angiography.These volumes were all calculated using the Osiris (version4.0; Unité d’Imagerie Numerique [Digital Imaging Unit]/Hôpitaux Universitaires de Genève [University Hospitalof Geneva] (UIN/HUG), Geneva, Switzerland) or LeksellGamma Plan.

Statistical analyses

Continuous variables except nidus volume and categoricalvaluables with more than three categories were dichoto-mized on the basis of their median values or the variables’statistical significances, i.e., age (≤30 years, >30 years),dose (≤14.5 Gy, >14.5 Gy), Spetzler–Martin grade (III andIV, V), longest nidus diameter (≤35 mm, >35 mm), numberof draining veins (1, ≥2), diameter of major draining vein(≤12 mm, >12 mm), and number of feeding arteries (1, 2and ≥3).

Factors potentially affecting nidus obliteration wereevaluated by performing a logistic regression for a univariateanalysis. For a multivariate analysis, we used a logisticregression model based on SAS software (version 9.0; SASInstitute, Cary, NC) to analyze the effect of radiosurgery,because the exact time of the obliteration was unclear (sinceobliteration was identified only after the fact, i.e., at the timeof cerebral angiography). Prospective analyses have sug-gested that the mode of the initial clinical presentation of anarteriovenous malformation may provide a marker for thesubsequent risk of haemorrhage. Patients who initiallypresented with haemorrhage had a higher rate of haemor-rhage during the subsequent course than did those presentingwith other symptoms [22, 38]. Therefore, for the overallanalysis of haemorrhage, the patients were grouped

according to their initial clinical presentation: those initiallypresenting with haemorrhage and those without haemor-rhage at presentation. Data on patients who underwent asecond radiosurgery or other treatment, e.g., microsurgicalarteriovenous malformation resection, were censored at thattime. Patients with one or more haemorrhages after initialpresentation were also censored at the first haemorrhageevent. To assess the effect of endovascular embolization onarteriovenous malformation obliteration and latency periodhaemorrhage, the patients were also regrouped into twosubgroups: radiosurgery with and radiosurgery withoutembolization. Kaplan–Meier methods were constructed forthe frequency of arteriovenous malformation haemorrhagein the two groups during follow-up. The significance ofgroup differences was assessed using a log-rank test. Inaddition, we constructed a Firth’s multivariate Cox propor-tional-hazards regression model, which included all modesof initial arteriovenous malformation presentation. Theannual haemorrhage rate was calculated from the numberof haemorrhages divided by the sum of the observationperiods. The observation period for haemorrhages wasdivided into the following three intervals: before radiosurgery,the latency period (the interval between radiosurgery andangiographic obliteration), and the postobliteration period (theinterval from angiographic obliteration to the end of thefollow-up period). To exclude the effect of preradiosurgicalembolization on haemorrhage, ‘before radiosurgery’ wasdefined as the period from diagnosis to initial treatment, suchas radiosurgery or preradiosurgical embolization. The func-tion outcome was assessed by KPS after radiosurgery.

Statistical significance was accepted for P values of lessthan 0.05.

Results

Follow-up and characteristics

The mean observation period from diagnosis to initialtreatment (radiosurgery or endovascular embolization) was0.5±0.9 months (range, 0–4.4), including the periodbetween diagnosis and referral to our hospital. The clinicalfollow-up periods of the 46 patients after initial radio-surgery ranged from 34.0 to 166.4 months (mean 78.1±38.1) and the mean neuroradiological follow-up period was63.4±35.9 months (range, 11.0–156.4). The mean arterio-venous malformation volume was 29.5 ml (range, 14.0–65.0). The mean dose to the arteriovenous malformationmargin was 14.1 Gy (range, 10–20 Gy). Four patientsrejected participation in a 3 year neuroradiological follow-up study, because their symptoms had disappeared and theyhad no difficulties in their daily life. At their last clinicalfollow-up, these four were reinstated in their occupation


and their KPS were all 100. These four of 46 patients wereexcluded from our analysis of the nidus obliteration ratebecause of their insufficient neuroradiological follow-up(11, 23, 24, and 25 months, respectively). However, theywere all included on the rate of latency period haemorrhagesince their CT or MRI at neuroradiological follow-up coulddetect the evidence of haemorrhage. Angiography withMRI of 33 of 42 patients was done at their 3-yearpostradiosurgical follow-ups, and remaining nine patientswere examined by MRI and MR angiography. Totalobliteration was observed using angiography/MRI in 11patients and using MRI/MR angiography in 16 patients.Two patients underwent microsurgical arteriovenous mal-formation resection because of latency period haemorrhageafter initial radiosurgery. Of the 24 arteriovenous malfor-mations with residual arteriovenous malformation con-firmed by angiography or MRI, 20 patients underwentrepeated radiosurgery using the GK system because ofobliteration failure based on follow-up angiography (Table 2).The rest four patients refused further treatment because theyhad no difficulties in their daily life and their KPS were all100. Second radiosurgery was performed at a median of40.8 months (range, 31.7–59.8) after the first radiosurgicalprocedure. Mean follow-up period after the second radio-surgery was 19.7±13.0 months (range, 6.2–48.0).

Arteriovenous malformation obliteration

Depending on the results of the angiography, completeobliteration was observed in 11 of 33 patients after the firstradiosurgery and three of four patients after the secondradiosurgery (Fig. 2) (Table 2). There were four cases inwhich a MRI demonstrated disappearance of the arteriove-nous malformation but there was no angiographic confir-mation after the first radiosurgery. When these patients arecounted as having complete obliteration of the nidus,complete obliteration was observed in 16 of 42 patientsafter the first radiosurgery and four of five patients after thesecond radiosurgery.

Of the four patients with 3-year angiographic follow-upafter the second radiosurgery, one experienced recanaliza-tion of the area previously obliterated by embolization; sheunderwent the third radiosurgery for the recanalized lesion(Fig. 1). Mean arteriovenous malformation volume at thesecond radiosurgery was 5.8 ml (range, 0.7–32.7), whichrepresents an 81% decrease in the mean arteriovenousmalformation volume at re-treatment and was significantlylower than the mean initial volume (Wilcoxon test, P=0.017). The mean marginal dose was 14.1±2.2 Gy (range,10–20) for the initial radiosurgery, and 16.1±2.7 Gy (range,12–21) for the second radiosurgery. Although 15 patientsdid not undergo angiography because of their follow-upperiod was less than 3 years after the second radiosurgery,they showed a significant reduction in nidus volume (mean4.8 ml; range, 0.5–26.8) at follow-up MRI (P=0.035;Fig. 2).

Factors significantly associated with a better obliterationrate were age (older than 30 years; odds ratio, 13.94; 95%CI, 1.20–190.76; P=0.010), dose (more than 14.5 Gy; oddsratio, 8.23; 95% CI, 1.32–50.48; P=0.037), and number offeeding arteries (≥3; odds ratio, 19.30; 95% CI, 1.13–340.76; P=0.048) (Table 3). The obliteration rates were notsignificantly different statistically between the LINACradiosurgery subgroup and the GK radiosurgery subgroup(log-rank test, P=0.554). The mode of initial clinicalpresentation also showed no significant effect for arterio-venous malformation obliteration (P=0.941).

Effect of endovascular embolization

Of the 46 patients, 25 patients were treated with radio-surgery plus preradiosurgical embolization and 21 weretreated with radiosurgery only. The mean follow-up periodwas 76.6±35.1 months (range, 37.8–130.5) in the non-embolization group and 74.3±33.7 months (range, 36.2–156.6) in the embolization group. There was no statisticallysignificant difference between the volumes at arteriovenousmalformation diagnosis of the 25 patients in the embolization

Table 2 Summary of radiosurgical outcome

First radiosurgery Second radiosurgery

Angiography MRI Angiography MRI33 patients 42 patients 4 patients 5 patients

Outcome No. of patients No. of patients No. of patients No. of patients

Obliteration 11 16 3 4Residual nidus 20 24 1b 1b

Microsurgical resectiona 2 2

a Two patients underwent a microsurgical arteriovenous malformation resection because of a latency period hemorrhageb Three year follow-up angiography after the second radiosurgery revealed recanalization of the area previously obliterated by embolization


group (mean 32.4±14.1 ml) and the volumes at arteriovenousmalformation diagnosis of the 21 patients (mean 26.5±10.8 ml) in the nonembolization group (Mann–Whitney Utest, P=0.124). The obliteration rates after initial radio-surgery were 42% in the nonembolization group and 31% inthe embolization group, with the difference being statisticallyinsignificant (P=0.392). Preradiosurgical embolization wasnot found to be associated with nidus obliteration in ourstudy.

Before radiosurgery, of the 25 patients who underwentendovascular embolization, three showed transient edema

around the nidus between 3 and 6 months after emboliza-tion. One patient experienced a subarachnoid haemorrhagecaused by arteriovenous malformation rupture duringembolization.

Haemorrhages during the latency period

No patient had a haemorrhage before radiosurgery (meanfollow-up, half a month). Haemorrhage during the latencyperiod after radiosurgery occurred in three patients in thehaemorrhage group and in five of those without previous

Fig. 1 Angiograms of a 23-year-old lady who presented withconduction dysphasia showing a left temporal arteriovenous malfor-mation with a preradiosurgical volume of 16.1 ml. Partial emboliza-tion had been performed previously. Anterior posterior views of theleft internal carotid artery (a–c). Before radiosurgery (a). Angiogram3 years after radiosurgery revealed partial obliteration of the

arteriovenous malformation and repeat radiosurgery was performed(b). Angiogram obtained 3 years after the second radiosurgeryrevealed recanalization of the area previously obliterated by emboli-zation (arrows point to recanalized area); she underwent the thirdradiosurgery (c)

Fig. 2 Initial and follow-up angiograms of a 30-year-old man whopresented with headache and right hemiparesis as a result of anintracerebral haemorrhage. Angiogram at the time of initial radio-surgery. The nidus volume was 29 ml, and the marginal dose to thearteriovenous malformation was 12 Gy (a). Angiogram 37 months

later at the second radiosurgery (arteriovenous malformation volume,9.8 ml; marginal dose, 17 Gy). Note partial obliteration in thearteriovenous malformation during the interval (b). Angiogramobtained 35 months after the second radiosurgery revealing completeobliteration of the arteriovenous malformation (c)


haemorrhage. The mean follow-up period was 73.3±45.5 months (range, 10.5–145.3) in the haemorrhage groupand 66.5±32.6 months (range, 6.4–147.7) in the non-haemorrhage group. The annual haemorrhage rates afterradiosurgery were 2.9% in the haemorrhage group and3.1% in the nonhaemorrhage group (Table 4). Haemorrhageduring the latency period after radiosurgery was not signifi-cantly associated with clinical presentation of haemorrhageas the initial symptom (P=0.941). Furthermore, the regres-sion model that included all modes of initial arteriovenousmalformation presentation did not show a significantassociation of latency period haemorrhage during follow-up. Actuarial estimates of the cumulative 5-year risk ofhaemorrhage after initial presentation were 17.7% (SE 9.3)in the haemorrhage group and 10.5% (SE 5.7) in thenonhaemorrhage group (Fig. 3a). The 75% of latency periodhaemorrhage occurred during the first 3 years after radio-surgery. The univariate risk analysis showed associationsbetween deep-seated nidus without cortical exposure (P=0.008), ventricular exposure (P=0.050), and the risk ofhaemorrhage on follow-up in the haemorrhage group. Thenumber of feeding arteries (P=0.094) and preradiosurgicalembolization (P=0.541) failed to reach significance. InFirth’s multivariate Cox proportional-hazards regressionmodel, no factor was found to be associated with latencyperiod haemorrhage. In the nonhaemorrhage group, multi-variate analysis identified Spetzler–Martin grade (III/VI, V)(hazard ratio, 0.01; 95% CI, 0.00–0.50; P<0.018), volume(hazard ratio, 0.82; 95% CI, 0.73–0.90; P<0.001), deep-seated nidus without cortical exposure (hazard ratio, 29.36;95% CI, 1.09–7,043.10; P=0.043), and preradiosurgical

embolization (hazard ratio, 28.03; 95% CI, 1.08–6,759.64;P=0.039) as independent prognostic factors for latencyperiod haemorrhage. Marginal dose was not identified asan independent prognostic factor. Preradiosurgical emboliza-tion increased the risk of haemorrhage for the nonhaemor-rhage group (hazard ratio, 28.03; 95% CI, 1.08–6,759.64;P=0.039), whereas it had no effect in the haemorrhagegroup. Data on predefined subgroups of patients wereanalyzed to determine whether the effect of preradiosurgicalembolization varied between subgroups. Latency periodhaemorrhage occurred in eight patients in the embolizationgroup, but no patients in the nonembolization group (Table 4)(Fig. 3b). The rate of latency period haemorrhage wassignificantly lower in the nonembolization subgroup than inthe embolization subgroup (P=0.004).

Of the eight patients who experienced latency periodhaemorrhage, five experienced a small amount of asymp-tomatic haemorrhage that was detected by MRI review.However, latency period haemorrhage was clinically sig-nificant in three patients; two of these underwent microsur-gical arteriovenous malformation resection during hematomaevacuation, and the other underwent hematoma evacuationonly. However, no patient died because of a latency periodhaemorrhage. At the last clinical follow-up, their median KPSwas 90 and ranged from 80 to 100.

Of the five patients with aneurysm, one experienceda latency period haemorrhage. However, the cause ofhaemorrhage was conclusively determined by angiogra-phy to be rupture of the arteriovenous malformation.These aneurysms had no impact on latency period haemor-rhage. No patient that achieved angiographically or MRI

Table 3 Factors associated with nidus obliteration

Univariate Multivariatea

Factor Odds ratio 95% CI Odds ratio 95% CI

Sex 4.02 0.71–26.95Age (30/>30) 12.23 1.80–82.71 13.94 1.20–190.76Volume 1.36 0.92–1.48Radiosurgical tool (GK/LINAC) 0.57 0.09–3.64Dose (14.5/>14.5) 5.32 1.13–23.97 8.23 1.32–50.48Spetzler–Martin grade [37] 0.31 0.06–2.13Cortical exposure 2.61 0.13–48.15Ventricular exposure 5.38 0.83–42.76Number of draining vein 0.69 0.12–4.90Maximum diameter of draining vein 1.00 0.10–13.76Number of feeding arteries (1, 2/≥3) 11.50 1.04–128.32 19.30 1.13–340.76Pre-radiosurgical embolization 0.60 0.11–3.42Pre-radiosurgical hemorrhage 2.31 0.21–35.65

CI confidence interval, GK gamma knife, LINAC linear acceleratora Owing to the redundancy of the factors used in the multivariate analysis by logistic regression model, univariate analysis was performed initially,and factors that were found to be statistically significant by the univariate analysis were then subjected to multivariate analysis


documented obliteration experienced a subsequent haemor-rhage. No patient experienced latency period haemorrhageafter the second radiosurgery.

Radiosurgery-related complications

Five patients developed transient regions of hyperintensesignals on T2-weighted images in surrounding normal brain

tissues after the first radiosurgery, and all patients wereasymptomatic. Two patients developed transient signalchanges on T2-weighted images after the second radio-surgery. Of these two patients, one experienced a mildheadache and required analgesics for 3 days. Signalchanges were found 10–16 months after radiosurgery andspontaneously disappeared without treatment. However, nopatient has experienced transient or permanent neurologicaldeficits at their final follow-up or was treated with steroidfor complications related to radiosurgery. In the haemor-rhage group, the KPS at last follow-up (mean 94±8) wassignificantly higher than the KPS at diagnosis (mean 81±18) (paired t-test, P=0.004). As in the haemorrhage group,the KPS at last follow-up (mean 98±3) was significantlyhigher than the KPS at diagnosis (mean 95±7) in thenon-haemorrhage group (P=0.031). No patient developeddelayed cyst formation, radiation necrosis, or radiosurgery-related death.

Discussion

Arteriovenous malformation obliteration

Until now, radiosurgery for large arteriovenous malforma-tion has been expected to be less effective than othermethods because doses are generally reduced to preventradiosurgery-related complications [24, 25, 29]. In commonwith other large arteriovenous malformation studies [24, 25,29, 35], our study showed a comparatively low obliterationrate of 33.3% after initial suboptimal-dose radiosurgery.Although initial radiosurgical treatment failed in 20patients, it did produce a substantial therapeutic effect (an81% reduction of volume). This volume reduction allowedthe administration of higher doses at a second radiosurgery.Higher radiation doses directly correlate with an increasedprobability of arteriovenous malformation obliteration [8].Although in early assessment of the obliteration rate afterthe second radiosurgery, three of four patients examined3 years after the second radiosurgery achieved obliteration(Table 2), the remaining patient, unfortunately, showed

Fig. 3 Kaplan–Meier life-table analysis of latency period hemorrhageduring the clinical course after radiosurgery. The two survival graphsare based on model estimates for haemorrhagic vs. nonhaemorrhagicpresentation (a) and embolization vs. nonembolization (b)

Table 4 Relation between preradiosurgical embolization and hemorrhage

Hemorrhage group (n=17) Non-hemorrhage group (n=29) Total

LPH (+) LPH (−) AHR (%) p value LPH (+) LPH (−) AHR (%) p value AHR (%) p value

Embolization subgroup (n=25) 3 10 5.1 0.541 5 7 7.7 0.007 6.5 0.004Non-embolization subgroup (n=21) 0 4 0 0 17 0 0Total 2.9 3.1 3.0 0.941

Data are numbers of patients unless otherwise specifiedAHR annual hemorrhage rate, LPH latency period hemorrhage


recanalization of an arteriovenous malformation treatedusing preradiosurgical embolization. As for the first radio-surgical outcome, all 15 patients who did not receiveangiography after the second radiosurgery showed adecrement in nidus volume at follow-up MRI.

Latency period haemorrhage

Many radiosurgical studies of arteriovenous malformationshave suggested that the haemorrhage risk during the latencyperiod decreases [21], remains unchanged [28] or evenincreases [15] compared with the natural course of thedisease. Nevertheless, if an adequate dose of radiation isdelivered at to the entire arteriovenous malformation, therisk of haemorrhage may be reduced without arteriovenousmalformation obliteration [6, 15, 21]. Some studies [13, 24]have found that a larger arteriovenous malformation size issignificantly associated with postradiosurgical haemorrhageand have suggested the possible causes of haemorrhageto be: (1) angiographic risk factors such as intranidalaneurysms, (2) an inherent tendency for larger arteriove-nous malformations to bleed, (3) inadequate treatment oflarge arteriovenous malformations resulting in an in-creased time at risk, and (4) partial treatment resulting inincreased arteriovenous malformation perfusion pressures.Our study showed a similar result; in our study, the smallerthe size of arteriovenous malformations, the lower the riskof haemorrhage after radiosurgery. To fully analyze theeffect of radiosurgery on haemorrhage, the risk of haemor-rhage after radiosurgery should be compared with the riskof haemorrhage before radiosurgery. However, because theobservation period before radiosurgery in our study washalf a month and no patient experienced a haemorrhage,the risk of haemorrhage after radiosurgery was assessedagainst other arteriovenous malformation studies. In patientsinitially presenting without haemorrhage, our study showedan annual haemorrhage rate of 3.1%, which is similar tothe 2.2–3.9% rate of annual haemorrhage seen in thecourse of untreated arteriovenous malformations [3, 22,38] and a comparatively low haemorrhage rate in radio-surgery for large arteriovenous malformations, unlikeother radiosurgical studies [13, 24]. However, in our study,the annual haemorrhage rate was slightly higher than1.5% for grade IV and V untreated arteriovenous malfor-mations [11]. By contrast, in the hemorrhage group, therisk of hemorrhage was significantly decreased afterradiosurgery compared with the untreated arteriovenousmalformation group [3, 22, 38]. We found that suboptimal-dose radiosurgery maintained or significantly decreasedthe risk of haemorrhage from arteriovenous malforma-tion, both during the latency period and after angio-graphic obliteration. This result should be interpretedwith caution, however, because latency period haemorrhage

did not occur after radiosurgery in the nonembolizationgroup.

Relation between haemorrhage and embolization

In the nonhaemorrhage group, preradiosurgical emboliza-tion was a strong and independent determinant of latencyperiod haemorrhage after radiosurgery. Moreover, the non-embolization subgroup did not have a subsequent haemor-rhage after radiosurgery in the haemorrhage group, even ifthis result lacked statistical power. Young et al. demon-strated that a lower transnidal pressure gradient betweenfeeding arteries and draining veins is present in largerarteriovenous malformations [43], and it was also shownthat flow dynamics were remarkably changed after embo-lization in arteriovenous malformations with a lower trans-nidal pressure gradient [10, 32]. It has been reported thatproximal brain-nutritive arteries in arteriovenous malforma-tions lose autoregulation because of chronic hypoperfusion[2], and the feeding arteries have abnormal endotheliumwith elastic and medial degeneration because of mechanicalstresses induced by long-standing high flow [1]. Thedemonstration of abrupt hemodynamic changes inducedby embolization gives additional credence to the theory ofnormal perfusion pressure breakthrough and to theories ofneurological change based on vascular steal phenomena[12]. If this pressure change is transmitted to a proximalfeeding artery or a brain-nutritive artery, haemorrhage orsevere vasogenic edema might occur [1, 10]. In our study,three patients showed temporarily severe edema, whichwas thought to be vasogenic edema induced by abrupthemodynamic alteration, around an arteriovenous malfor-mation on MRI at 3 to 6 months after preradiosurgicalembolization. It seems that the lower the pressure offeeding arteries, the more likely that haemorrhages afterembolization will occur, owing to remarkable hemody-namic alterations [36]. In addition, progressive thickeningof the intimal layer and partial or complete thrombosisof the irradiated vessels after radiosurgery may gradu-ally augment the hemodynamic changes [5, 34]. Afteranalyzing the studies described above and our results,hemodynamic deteriorations induced by preradiosurgicalembolization are suggested as a possible cause of haemor-rhage after radiosurgery. Moreover, preradiosurgical em-bolization tends to give rise to new neurological deficitsand recanalization, and make it more difficult to delineatethe true nidus during radiosurgical treatment planning[9, 23, 26].

In contrast to our experience, Veznedaroglu et al. [42]reported that the reduction in arteriovenous malformationsize by the embolization increased the obliteration rate withno latency period haemorrhage after a fractionated stereotacticradiotherapy. Although our conclusion about preradiosurgical


embolization is currently debatable, embolization for volumereduction in advance of radiosurgery has a very limited role inradiosurgery.

Staged-volume radiosurgery

Colombo et al. [6] found that the haemorrhage risk forpartially treated arteriovenous malformations was greater thanthat for completely irradiated arteriovenous malformations.On the other hand, Pollock et al. [30] reported that followingstaged-volume radiosurgery of arteriovenous malformationswith a median volume of 17.4 ml, the incidence of latencyperiod haemorrhage was 0%. In their study, they put anemphasis on the importance of precise dose planning toimprove patient outcomes. Sirin et al. [35] recently evaluatedtheir clinical outcome and complications in 28 patients withlarge arteriovenous malformations after staged-volume radio-surgery. Of 21 patients followed for more than 36 months,who allowed an evaluation of the obliteration rate, seven(33.3%) had complete arteriovenous malformation oblitera-tion. Four patients (14%) had a hemorrhage after radio-surgery; two died and two patients recovered with permanentneurological deficits. Out of these four patients, threeunderwent previous embolization. Worsened neurologicaldeficits developed in one patient. Four (14%) patientsdeveloped peri-arteriovenous malformation imaging changesrequiring steroid usage.

Gross features of an arteriovenous malformation includethe absence of a capillary bed and single or multiple directarteriovenous connections that permit high-flow arteriove-nous shunting through small feeding arteries. Over time,this high-flow shunt produces secondary changes in thestructure of the feeding and draining vessels. Althoughmicroscopic features of arteriovenous malformations arevariable and depend on its location, venous elements havethin collagenous walls, whereas arterial feeders have hyper-plasic muscular elastic walls associated with fibroblasts [20].Although the information on the early physiological andpathological alterations of arteriovenous malformation afterradiosurgery has not been demonstrated, Major et al. [19]found that abolition of potassium-induced arterial relaxationoccurred as early as 24 h after irradiation whilst 1 year laterthis reaction seemed to recover or remained active to18months according to the radiosurgery of rat middle cerebralarteries. They demonstrated reduction of contractile capabilityof the irradiated normal vessels while the vessels remainedpatent in the early stage after radiosurgery. Although theprecise reasons for the differences in each haemorrhage riskduring the latency period among these staged-volume radio-surgery studies [6, 27, 35] are not explained, partial separatedirradiation may induce hemodynamic changes within thearteriovenous malformation to nonirradiated regions evenin the early stage after radiosurgery.

Hypofractionated stereotactic radiotherapy

In the study of Zabel-du Bois et al. [44], 15 patients weretreated with hypofractionated stereotactic radiotherapy(median total dose, 26 Gy; median dose per fraction,6.5 Gy) and the angiographically proven obliteration rate inlarger than 10 ml of arteriovenous malformations (medianvolume, 27 ml) was 33% (5/15) 4 years after treatment. Ifwe assume an α/β ratio of 2.0 Gy for normal tissue, whichis widely accepted with regard to late effects afterradiotherapy, a dose of 26.0 Gy in four fractions wouldhave the same effect as 13.9 Gy in a single fraction.Lindvall et al. [18] also reported that patients were treatedwith hypofractionated stereotactic radiotherapy and theangiographically proven obliteration rate in arteriovenousmalformations larger than 10 ml was 70% (7/10) 5 yearsafter treatment. However, 7% of patients developedradiological changes suggesting radiation necrosis and theyall had permanent neurological deficits. Vernimmen et al.[41] reported that the obliteration rate in patients witharteriovenous malformations larger than 14 ml treated usinghypofractionated stereotactic proton beam radiotherapy was43% (12/28). Obliteration was confirmed by angiography inthree, CT in eight, and MRI in five. In their follow-upexaminations, they observed 29% temporary (requiringsteroids) and 14% permanent adverse radiation effects inpatients with arteriovenous malformations larger than14 ml. The benefit of hypofractionated stereotactic radio-therapy depends on the relationship between the α/β ratiosof arteriovenous malformations and the normal late-responding normal brain tissue in the irradiated area. Ifthe arteriovenous malformation has a somewhat higher α/βratio than normal tissue, there is a potential for therapeuticgain with hypofractionated stereotactic radiotherapy, allow-ing a higher dose of radiation than a single fraction can[44]. However, the actual α/β ratios of arteriovenousmalformations and normal brain tissue are not well known.Although the potential benefit of hypofractionated stereo-tactic radiotherapy in large arteriovenous malformations hasnot yet been clearly determined, hypofractionated stereo-tactic radiotherapy is one option to treat large arteriovenousmalformations.

Radiosurgery-related complications

At the time of the final radiological and clinical follow-ups,no patient had a permanent or transient neurological deficit,and no radiosurgery-related death occurred in the patientswho were given the suboptimal-dose radiosurgery in ourstudy. Moreover, the functional outcome was improvedafter radiosurgery, regardless of initial presentation. Thereasons why we experienced so few radiosurgery-relatedcomplications could be: (1) prescribed marginal doses were


10–15% less than the 1% complication line of Kjellberg etal. [15] for arteriovenous malformation; (2) radiation doseswere occasionally reduced, depending on arteriovenousmalformation volume and location or patient status; and (3)suboptimal-dose radiosurgery induced less hemodynamicstress due to blood flow redistribution compared with staged-volume radiosurgery [6].

The best-known treatment for arteriovenous malformationis surgery. For large arteriovenous malformation, however,surgery is far less appealing because it is associated withsignificantly higher morbidity and mortality rates. On theSpetzler–Martin scale, morbidity and mortality rates forpatients with grade IV and grade V (183 patients, 9.0–38.8%and 0–9.0%) were higher than those for patients with grade Ito grade III (632 patients, 2.0–6.3% and 0–2.0%) after surgery[4]. In a study of 201 patients who had a total of 339procedures of endovascular embolization, 2% died and 9%had permanent neurological deficits [39]. From a treatment-related morbidity and mortality point of view, the outcomefor patients treated with suboptimal-dose radiosurgery inour study compares favorably with the outcome in othertreatment method groups.

Our study has some limitations. The gold standard forevaluating the effect of radiosurgery would be a random-ized trial comparing a group undergoing radiosurgery witha group receiving no treatment. However, we performed aretrospective observational study and did not include acontrol group of patients. The small cohort and lack of long-term follow-up after second radiosurgery did not make it wellsuited to an assessment of the outcomes of radiosurgery.

In conclusion, radiosurgery may be a safe and effectivealternative treatment method for large arteriovenous mal-formations. In addition, the well-selected use of preradio-surgical embolization may increase the safety and efficacyof radiosurgery. However, additional long-term follow-upinformation on a larger cohort is required to determinemore accurately the value of suboptimal-dose radiosurgery.

Acknowledgements This study was partially supported by grantsfrom the Clinical Research Institute, Seoul National UniversityHospital and the Korea Brain and Spinal Cord Research Foundation.The funding sources had no role in study design, data collection, dataanalysis, data interpretation, or writing of the report. We thank ByungJoo Park, M.D. and Medical Research Collaborating Center SeoulNational University Hospital for their assistance in our statisticalanalysis. Moon Hee Han, M.D. helped us to review the neuro-radiologic findings of large cerebral arteriovenous malformations.

Conflicts of interest notification The authors have no conflicts ofinterest to declare.

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Comment

Stereotactic radiosurgery for large cerebral arteriovenous malformation

Gamma Knife surgery has been very successfull at treating small tomedium sized arteriovenous malformations (AVM’s). Obliteration ratesfor AVM’s less than 3 cm in maximal diameter are approximately 80 to85%. However, large AVM`s are less likely to be “cured” by singlefraction stereotactically delivered radiosurgery and such treatment isattended by higher complication risks: The authors could demonstratethat preradiosurgical embolization increased significantly the risk ofhaemorrhage for their nonhaemorrhage subgroup, whereas it had noeffect on the haemorrhage subgroup. In addition, latency periodhaemorrhage occurred significantly more in their embolization sub-group, but in no patient in the nonembolization subgroup.

Large or even giant cerbrovascular formations need therefore specialattentions as their clinical behaviour is different from small or mediumsized lesions. It is this fact that the makes this study of special interest.The authors results may let us conclude that for large AVMs, multipleembolization procedures may be required to avoid changing blood flowpatterns in the brain too rapidly or drastically (1). This may underlinethat the treatment of brain AVMs can only be greatly enhanced byadopting a team approach utilizing combined modality therapy. Usingthis strategy, a treatment plan is devised to offer the lowest risk yethighest chance of obliterating the lesion.

References

1. Schaller B, Graf R. Cerebral venous infarction: The pathophysio-logical concept. Cerebrovasc Dis 2004; 18:179–188

B. SchallerStockholm


radiosurgery for large cerebral arteriovenous malformations

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