KEY WORDS: Arteriovenous malformation, Complications, Outcome, Radiosurgery

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1 CLINICAL STUDIES ARTERIOVENOUS MALFORMATIONS AFTER LEKSELL GAMMA KNIFE RADIOSURGERY: RATE OF OBLITERATION AND COMPLICATIONS Roman Liščák, M.D. Department of Stereotactic and Radiation Neurosurgery, Vilibald Vladyka, M.D. Department of Stereotactic and Radiation Neurosurgery, Gabriela Šimonová, M.D. Department of Stereotactic and Radiation Neurosurgery, Dušan Urgošík, M.D. Department of Stereotactic and Radiation Neurosurgery, Josef Novotný, Jr., Ph.D. Department of Stereotactic and Radiation Neurosurgery, Ladislava Janoušková, M.D. Department of Radiology, OBJECTIVE: Although relevant information exists regarding the chance of obliterating arteriovenous malformations (AVMs) using radiosurgery, the overall chance of cure after gamma knife radiosurgery is usually only extrapolated from a portion of all monitored patients. This chance and the risks involved in radiosurgery, including repeat treatment when necessary in a defined population of treated patients, were analyzed in our study. METHODS: Between October 1992 and June 2000, gamma knife radiosurgery was performed on 330 patients with AVMs. The volume of the AVM nidus ranged from 0.15 to 28.6 cm 3 (median, 3.9 cm 3 ). When complete obliteration was not achieved within 3 years, repeat radiosurgery was performed on 76 patients. The volume of the nidus for the second treatment ranged from 0.09 to 16.8 cm 3 (median 2.9 cm 3 ). The result was reviewed in 300 (91%) patients after the first round of treatment and in 68 (89.5%) after the second round of treatment. RESULTS: AVM obliteration was achieved in 222 (74%) patients after the first round of radiosurgery and in 47 (69%) after the second. The overall chance of cure was 92% (269 patients). Final angiography verified complete obliteration by 12 to 96 months (median, 25 mo) after initial radiosurgery. Smaller volume AVMs and the application of a higher radiation dose resulted in a higher chance of obliteration. The risk of rebleeding after radiosurgery was 2.1% annually until full obliteration, and the overall mortality from rebleeding was 1%. The risk of permanent morbidity after the first and second radiosurgery treatments were 2.7 and 2.9%, respectively. The cumulative risk of morbidity in both groups of patients was 3.4%. CONCLUSION: Although one-quarter of the patients required that the treatment be repeated, gamma knife radiosurgery can offer a high cure rate for patients treated for AVMs with a low risk of morbidity and mortality from rebleeding during the latent period. KEY WORDS: Arteriovenous malformation, Complications, Outcome, Radiosurgery Neurosurgery 60: , 2007 DOI: /01.NEU A Josef Vymazal, M.D. Department of Radiology, Reprint requests: Roman Liščák, M.D., Roentgenova 2, Prague 5, Czech Republic. Roman.Liscak@homolka.cz Received, October 23, Accepted, January 19, Radiosurgery offers a minimally-invasive treatment, but at the cost of the delay between treatment and complete obliteration, usually reported to be between 1 and 3 years after the treatment (8, 11 13, 18, 21, 29, 33, 34, 42, 43, 53, 60, 67, 73). This latent period brings with it two inherent handicaps. First, the risk of rebleeding remains the same as in an untreated patient until complete obliteration is achieved (22, 54, 57), although some decrease of this risk before obliteration has also been reported (32). Second, the latent period of several years from the treatment to the cure does not allow evaluation of the treatment outcome in all patients for many reasons not related to the treated disease. Thus, the reported result and effectiveness of radiosurgery could be impacted by the low proportion of patients undergoing a final evaluation of treatment success. More precise awareness of the results is advisable for the decision making process on arteriovenous malformation (AVM) management, in which several treatment options (e.g., open microsurgery, radiosurgery, embolization, and observation) are possible. NEUROSURGERY VOLUME 60 NUMBER 6 JUNE

2 LIŠČÁK ET AL. MATERIALS AND METHODS Radiosurgery was performed between October 1992 and June 2000 at, using the Leksell gamma knife model B (Elekta Instruments AB, Stockholm, Sweden) on 330 consecutive patients with AVMs. The stereotactic frame was fixed to the patient s head under local anesthesia (general anesthesia was generally used for children younger than 12 years of age) and the position of the frame was adjusted on the head according to the location of the AVM in the brain to bring the nidus of the AVM closer to the center of the stereotactic system. For the stereotactic localization of the AVMs, angiography alone was used on 118 patients, angiography plus computed tomography (CT) was used on 19 patients, and angiography with magnetic resonance imaging (MRI) was used on 192 patients. MRI alone was performed on only one patient. Since 1995, angiography plus MRI (Magnetom Expert 1T; Siemens, Erlangen, Germany) has been routinely used for the stereotactic localization of AVMs: turbo spin echo (fast spin echo) proton density T2-weighted, fast low angle shot with a short repetition time (TR) (e.g., repetition time, 168; echo time, 12; flip, 50) and a thickness of 3 mm was used in both the axial and coronal planes. Before 1994, the Kula planning system (Elekta InstrumentsAB) was used to plan gamma knife radiosurgery for 73 patients; subsequently, the Gamma Plan planning system (Elekta InstrumentsAB) was used for 257 patients. The male-to-female ratio was 1.17:1. The age of the patients ranged from 3 to 78 years (median, 35 yr). Previous microsurgical resection was performed on 64 (19.4%) patients, embolization was performed on 58 (17.6%) patients (median, 2; range, 1 5 embolizations on one patient), fractionated radiotherapy was performed on six (1.8%) patients, and proton therapy using cyclotron was performed on one patient. Seven of these patients had undergone a combination of surgery plus embolization before the gamma knife treatment, three patients had undergone fractionated radiotherapy plus surgery, and one patient had undergone embolization and fractionated radiotherapy. Gamma knife radiosurgery was the primary treatment for 215 (65.2%) patients. For the localization of the AVM and the Spetzler grade, see Tables 1 and 2. The maximal diameter of the AVM nidus ranged between 0.6 and 6.1 cm (median, 2.2 cm). The volume of the AVM nidus ranged from 0.15 to 28.6 cm 3 (median, 3.9 cm 3 ). In cases in which only angiography was available for stereotactic localization (118 patients), the volume of the nidus was calculated from the diameters of the nidus as measured on stereotactic angiography and approximated as ellipsoid. The volume in the rest of the patients was measured directly by delineating the AVM s nidus on the CT or MRI used for stereotactic localization. The marginal dose to the AVM nidus was 40 to 90% (median, 50%) isodose and ranged from 8 to 32 Gy (median, 20 Gy). The relation between the AVM nidus volume and dose to margin is shown in Figure 1. The dose to the maximum ranged between 18 and 60 Gy (median, 38 Gy). The number of isocenters used to cover the lesion ranged from 1 to 12 (median, 3); a TABLE 1. Arteriovenous malformation localization Localization No. Parietal 83 Occipital 69 Temporal 54 Frontal 39 Thalamus 22 Cerebellum 21 Corpus callosum 17 Basal ganglia 12 Brain stem 8 Intraventricular 5 TABLE 2. Spetzler-Martin arteriovenous malformation classification Grade No. I 39 (11.8%) II 156 (47.3%) III 100 (30,3%) IV 35 (10,6%) V 0 FIGURE 1. Graph showing the relation between AVM nidus volume and dose to margin. Patients with AVM nidus obliteration are indicated. 4-mm collimator was used in 3.5% of isocenters, an 8-mm collimator was used in 34%, a 14-mm collimator was used in 44.5%, and an 18-mm collimator was used in 18%. In cases in which obliteration was not achieved 3 years after radiosurgery, gamma knife radiosurgery was repeated. The volume of the nidus for the second treatment ranged from VOLUME 60 NUMBER 6 JUNE

3 RADIOSURGERY OF ARTERIOVENOUS MALFORMATIONS to 16.8 cm 3 (median, 2.9 cm 3 ). The marginal dose for the second treatment ranged between 12 and 25 Gy (median, 18 Gy) and was delivered on a 50 to 90% (median, 50%) isodose. The dose to the maximum ranged from 20 to 50 (median, 34 Gy); the number of isocenters ranged from 1 to 12 (median, 3). To prove complete AVM obliteration, digital subtraction angiography was considered mandatory. Before the installation of in-house MRI scanners in 1995, angiography was performed annually until the complete obliteration was verified. Later, angiography was performed after the disappearance of the flow void on MRI scans, which were performed annually. In the case of complications, CT or MRI scans were performed when there was a suspicion of rebleeding or postirradiation edema. Once complete obliteration of the AVM was verified by angiography, only symptomatic patients continued to be followed by written inquiries until their symptoms remained stable. MRI scans were performed after the complete obliteration only in cases in which the clinical status of the patient was impaired. As a rule, the patients were invited to our hospital for follow-up MRI scans or angiography. In the case of foreign patients, referring doctors were asked to perform follow-up examinations and send the data to our department for final evaluation. All treatment parameters and follow-up data were entered into a prospective database. RESULTS We succeeded in performing control angiography to evaluate the result of gamma knife radiosurgery of AVMs in 90% of the patients after both the first and the repeated gamma knife radiosurgical procedures, with the latter being performed in cases in which the initial treatment did not lead to complete obliteration of the AVM. The follow-up period ranged from 1 to 118 months (median, 38 mo). Follow-up was terminated within 3 years of the treatment when complete obliteration was achieved early or in the event of fatal complication from rebleeding (one patient died 1 mo after radiosurgery as a result of rebleeding). Twenty-one of the 330 patients were lost to follow-up after the first treatment (neither the patient nor the referring physician cooperated during the follow-up period) and nine patients died of unrelated causes 7 to 44 months after treatment. Thus, 300 patients (91%) remained for evaluation of the results of the first gamma knife treatment. Seventy-six patients underwent a second gamma knife radiosurgery treatment. Four of these were lost to follow-up and four died of unrelated causes before the result of the treatment could be evaluated. Sixty-eight patients (89.5%) remained for evaluation of the results after the second gamma knife treatment, and the follow-up period in this subgroup ranged from 51 to 118 months (median, 73.5 mo). Obliteration of AVMs Control angiography revealed complete obliteration after the first gamma knife radiosurgery in 222 patients, representing 74% of the 300 patients available for evaluation. It was not possible to monitor the process of obliteration continuously and the results were usually evaluated annually, with not all patients attending every annual follow-up examination. Table 3 shows the number of patients with completely obliterated AVMs as proven by angiography in 1-year intervals. Angiography was not mandatory for the diagnosis of patent and unobliterated AVMs, in which case MRI scans were sufficient. The obliteration rate was calculated for the group of patients with known results in respective intervals after the treatment. If the result was not available at the annual interval, two theoretical alternatives were postulated: that the obliteration was not complete in all patients with unknown results, which would represent the worst theoretical result or that obliteration could theoretically be complete in all of them, which could indicate the best result (see columns A and B in Table 3). The narrow interval between A and B gives the precise result and the obliteration rate 3 years after the first gamma knife radiosurgery treatment lies within the 70.3 and 72.6% interval. For the obliteration rate after the second gamma knife radiosurgery treatment, see Table 4. The obliteration rate 3 years after the second gamma knife radiosurgery treatment lies within the 61.8 to 66.2% interval. Finally, 47 (69%) patients had AVMs obliterated after the second gamma knife radiosurgery treatment. There were 292 patients available for the final evaluation (30 patients were lost to follow-up or died of unrelated causes after the first radiosurgery and eight were lost or died after the second one). Complete obliteration of AVM after the first and second gamma knife radiosurgery treatments was achieved in 269 patients, representing a success rate of 92.1%. Final angiography, including patients with repeated treatment, verified complete obliteration 12 to 96 months (median, 25 mo; average, 32.6 mo) after the initial gamma knife radiosurgery treatment. Rebleeding after Radiosurgery Before radiosurgery, bleeding from AVMs occurred in 207 patients (63%). The number of bleedings in a single patient ranged between one and seven episodes, with a median of one bleeding episode. A total of 294 bleedings represented a 2.5% annual risk of bleeding before the gamma knife treatment in 11,770 patient-years. Rebleeding was observed in the latent period before AVM obliteration in 19 patients 1 to 55 months (median, 15 mo) after the initial radiosurgery treatment. Sixteen patients experienced rebleeding after the first treatment, and three patients experienced rebleeding after the second radiosurgery treatment, representing a 2.1% annual risk of rebleeding after gamma knife radiosurgery in a total of 905 follow-up years. The neurodeficit after rebleeding impaired in seven patients, and three patients died as the consequence of the rebleeding, which represented a 1% mortality risk. Morbidity Neurodeficit caused by the AVM was detected before gamma knife treatment in 157 patients (52.3%). In 70 (44.6%) patients, this neurodeficit after gamma knife radiosurgery improved within 6 to 41 months (median, 8 mo). The neurodeficit wors- NEUROSURGERY VOLUME 60 NUMBER 6 JUNE

4 LIŠČÁK ET AL. TABLE 3. Arteriovenous malformation obliteration after the first gamma knife radiosurgery treatment in 300 evaluated patients a Years after Total Total not Result Obliteration A B 1st GKS obliterated obliterated not known rate (%) (%) (%) a GKS, gamma knife radiosurgery. Column A indicates the theoretical premise that all patients with unknown results still had patent arteriovenous malformations. Column B indicates the theoretical premise that arteriovenous malformation obliteration was accomplished in all patients with unknown results. TABLE 4. Arteriovenous malformation obliteration after the second gamma knife radiosurgery treatment in 68 evaluated patients a Years after Total Total not Result Obliteration A B 2nd GKS obliterated obliterated not known rate (%) (%) (%) a GKS, gamma knife radiosurgery. Column A indicates the theoretical premise that all patients with unknown results still had patent arteriovenous malformations. Column B indicates the theoretical premise that arteriovenous malformation obliteration was accomplished in all patients with unknown results. ened after the first radiosurgery treatment in 24 (8%) patients within 6 to 57 months (median, 13.5 mo). The cause of morbidity was collateral edema induced by radiosurgery in 17 patients and rebleeding in seven patients. Neurodeficit later resolved in 16 patients within 12 to 63 months (median, 23.5 mo) after radiosurgery, which represented a 2.7% risk of permanent morbidity. In the case of repeated gamma knife radiosurgery, morbidity was observed in another two patients (one case of rebleeding and one of collateral edema), representing a 2.9% risk of repeated radiosurgery. Finally, morbidity was observed in 10 patients (eight after the first treatment and two after the second treatment), which represented a cumulative risk of 3.4% in the group of 292 patients available for evaluation. Impairment of Karnofsky Performance Scale (KPS) score was observed in 17 patients. The KPS score before the treatment ranged 30 to 100% (median, 90%). After treatment, the KPS score decreased in 17 patients to 10 to 40% in 4 patients by 54 months (median, 12 mo) after the treatment. Impairment of KPS resolved in nine patients and remained permanently decreased in eight patients (median decrease, 20%). Five of these patients experienced impaired KPS scores after rebleeding. On the other hand, the KPS scores improved after the treatment in 109 patients by 10 to 40% (median, 10%) within 4 to 60 months (median, 12 mo) after treatment. Epilepsy Epilepsy was detected in 105 patients before radiosurgery. Termination of the seizures or improvement in seizure frequency was observed in 44 patients (41.9%) 1 to 60 months (median, 12 mo) after radiosurgery. A worsening of epilepsy after radiosurgery was detected in 12 patients (4%) 5 to 26 months (median, 12 mo) after radiosurgery; collateral edema was detected in eight patients. This impairment subsequently resolved in 10 patients between 12 and 36 months (median, 20.5 mo) after radiosurgery. Two patients with persistent impairment of epilepsy represented a risk of 0.7%. Postirradiation Collateral Edema Edema was detected by MRI scans in 64 patients (21.3%) within 2 to 36 months (median, 12 mo) after the procedure. Edema was detected within 1 year of radiosurgery in 78% of the patients and in only one patient after 2 years. Edema was symptomatic in a minority (23 patients), representing a 7.7% morbidity rate. Antiedematic corticotherapy was prescribed in 22 patients for a period of 1 to 10 months (median, 2 mo). Edema later resolved in 47 of these 64 patients 5 to 50 months (median, 24 mo) after the treatment and symptoms resolved in 17 out of 23 patients a median of 18 months after the treatment. Edema was detected in two out of 68 patients (2.9%) after a period of 12 or 48 months after the repeated treatment. Edema was symptomatic in only one patient, and there was no need for corticoid administration in that case. Edema later resolved in one patient within 1 year. Therapeutic Intervention after the First Radiosurgery Treatment Gamma knife radiosurgery was repeated in 76 patients (23%) because complete obliteration was not achieved within 3 years of the first treatment. The volume of the nidus for the second treatment was reduced by partial obliteration after the first treat VOLUME 60 NUMBER 6 JUNE

5 RADIOSURGERY OF ARTERIOVENOUS MALFORMATIONS ment by 0 to 94% (median, 61%); only eight out of 76 patients showed no reduction of the nidus after the first treatment. The second gamma knife radiosurgery treatment was performed 25 to 66 months (median, 38 mo) after the first procedure. Treatment was performed within less than 3 years only in cases in which a new nidus had developed (recanalization after previous embolization), which was observed in three patients. In one patient, a ventriculoperitoneal shunt was inserted because of hydrocephalus 48 months after radiosurgery; two patients underwent open surgery after rebleeding. In one of them, an organized hematoma with expansive behavior was revealed. Statistical Analysis Eleven different factors were proposed to assess their influence on AVM gamma knife radiosurgery. These factors were patients sex, patients age, previous surgical operation, previous embolization, previous hemorrhage of AVM, AVM volume, AVM location, Spetzler grade, AVM imaging (angiography alone versus angiography plus CT or MRI), AVM maximal dose, and AVM marginal dose. Altogether, four different events were studied as potentially dependent on these proposed factors. The events observed after gamma knife irradiation were as follows: AVM nidus obliteration, neurodeficit improvement, edema occurrence, and morbidity. To point out factors influencing the time dependence of the above-listed events, univariate and multivariate statistical analyses were used. Univariate analyses were performed using Kaplan-Meier statistics with the Log rank test. Multivariate analysis was performed with the Cox proportional hazards model using the backward stepwise (conditional likelihood ratio) method. Analyses were performed using SPSS statistical software (version 10.0; SPSS, Inc., Chicago, IL). Variables with significant P values (P 0.050) in at least one of two actuarial analyses were considered possible risk factors for the event. Factors having significant influence on studied events are indicated and significant P values are listed for both univariate and multivariate analyses in Table 5. Relative risk Exp(B) and 95% confidence intervals (95% CI) for Exp(B) are also presented for multivariate statistical analysis further in the text. AVM Nidus Obliteration The overall cumulative number of patients with AVM nidus obliteration after the first and second treatments is shown in Figure 2. A significantly higher incidence of AVM nidus obliteration was observed in male patients (P 0.011; Cox, Exp(B) 0.707; 95% CI, ), in patients with previous hemorrhage (P 0.049; Cox, Exp(B) 1.304; 95% CI, , P Log rank), in patients with an AVM volume less than 10.0 cm 3 (P 0.001; Cox, Exp(B) 0.646; 95% CI, , P Log rank), in patients with AVM Spetzler Grade I and II (P 0.003; Cox, Exp(B) 0.765; 95% CI, ; P Log rank), in patients in whom the dose to maximum in the AVM nidus was higher than 35 Gy (P Log rank), and in patients in whom the dose to margin in the AVM nidus was higher than 19 Gy (P Log rank). Neurodeficit Improvement after Gamma Knife Radiosurgery Significantly higher neurodeficit improvement after gamma knife radiosurgery was observed in patients younger than 25 years old (P Log rank) and for patients with previous hemorrhage (P 0.003; Cox, Exp(B) 2.776; 95% CI, ; P Log rank). Edema Occurrence after Gamma Knife Radiosurgery A significantly higher edema occurrence was observed after gamma knife radiosurgery for patients older than 50 years old (P 0.035; Cox, Exp(B) 1.448; 95% CI, ; P Log rank), for patients with no previous surgery (P 0.043; Cox, Exp(B) 0.297; 95% CI, ; P Log rank), for patients with no previous embolization (P 0.002; Cox, Exp(B) 0.257; 95% CI, ; P Log rank), for patients with no previous hemorrhage (P 0.001; Cox, Exp(B) 0.340; 95% CI, ; P Log rank), for patients with a AVM nidus volume between 5.0 and 10.0 cm 3 (P Log rank), and for patients in whom the dose to the margin in the AVM nidus was less than 23 Gy (P 0.003; Cox, Exp(B) 0.935; 95% CI, ; P Log rank). Morbidity A significantly higher morbidity was observed after gamma knife radiosurgery for patients with no previous embolization (P 0.011; Cox, Exp(B) 0.204; 95% CI, ) and for patients with an AVM nidus volume larger than 10.0 cm 3 (P Log rank). DISCUSSION Obliteration of AVM after Radiosurgery Unlike microsurgery or embolization, AVM obliteration after gamma knife radiosurgery cannot be evaluated immediately after the procedure. For many reasons, this makes it impossible to evaluate the effectiveness of the treatment in all patients (e.g., a patient can refuse to participate in follow-up, can move without providing a new address, or can die of unrelated causes). Therefore, the proportion of patients available for the final evaluation usually ranges from 36 to 82% (11, 12, 29, 34, 55, 62, 77). We succeeded in following 90% of our patients after treatment. The latency period before AVM obliteration after radiosurgery causes some problems in the interpretation of therapeutic results. We do not know the exact date on which the obliteration occurred before the last follow-up examination at which it was recorded. This makes the interval of latency until obliteration referred to in the literature an overestimate (68), and loss of a significant proportion of the treated patients for the final evaluation can make the results imprecise (26). Published results are, however, consistent, although the portion of patients lost to follow-up differs (Table 6). Another limitation we encountered was the difficulty in obtaining precise results for the obliteration rate at 1-, 2-, and 3- year intervals after radiosurgery because not all patients were NEUROSURGERY VOLUME 60 NUMBER 6 JUNE

6 LIŠČÁK ET AL. TABLE 5. Overview of studied events and factors a AVM obliteration Neurodeficit improvement Edema occurence Morbidity Sex P (Cox) X X X Age X P (Log rank) P (Cox) X P (Log rank) Previous surgery X X P (Cox) X P (Log rank) Previous embolisation X X P (Cox) P (Cox) P (Log rank) Previous hemorrhage P (Cox) P (Cox) P (Cox) X P (Log rank) P (Log rank) P < (Log rank) AVM volume P < (Cox) X P < (Log rank) P (Log rank) P < (Log rank) AVM location X X X X Spetzler grade P (Cox) X X X P < (Log rank) AVM imaging X X X X Dose to maximum P < (Log rank) X X X Dose to margin P < (Log rank) X P (Cox) X P (Log rank) a AVM, arteriovenous malformation. FIGURE 2. Kaplan-Meier cumulative curve for patients with AVM nidus obliteration after both first and second gamma knife radiosurgery treatments. followed annually. The extremes between the results observed during the follow-up period are that all patients who were not followed were or were not cured. These two figures (optimistic and pessimistic) mark the boundaries of the interval within which lies the truth. The high percentage of monitored patients makes this interval narrow and the final results more precise. The width of this interval 3 years after the gamma knife radiosurgery was 2.3% after the first and 4.4% after the second treatment in our series (Tables 3 and 4). The Spetzler-Martin AVM grading system, which considered the diameter of the AVM nidus, its localization in the eloquent areas, and the type of venous drainage (64), proved to be apposite for the prognosis and result of the microsurgical resection (6, 47). This scheme has limited relevance for the prognosis and the results of radiosurgery; thus, another classification for the purpose of radiosurgery was proposed, whereby the volume and location of AVM and the age of the patient were the most significant variables for determining positive treatment outcomes (1, 33, 52, 55). The volume of the nidus is more decisive than its maximal diameter (33), and a smaller volume allows for a higher dose of radiation, which is another significant factor for the successful AVM obliteration after radiosurgery (18, 33, 77). Apart from targeting error, an increasing AVM volume, decreasing treatment dose, and increasing Spetzler-Martin grade are the main reasons for treatment failure in radiosurgery (16). In our series, we observed that a higher obliteration rate was achieved for smaller volume AVMs and a higher minimal and maximal dose. Higher success was also observed in patients with Spetzler-Martin Grade I and II AVMs, which is attributed to smaller volume AVMs in this group. A higher obliteration rate in patients with bleeding also relates to AVM volume because, although the median volume of AVMs with a history of bleeding was 2.9 cm 3, the median volume in AVMs with no history of bleeding was 5.8 cm 3. The obliteration rate was statistically higher in men, but the distribution of volume in men (median, 3.65 cm 3 ) and women (median, 3.75 cm 3 ) was similar, as was the marginal dose; the median marginal dose was 21 Gy in men and women. We can only hypothesize that men have a higher vascular sensitivity, 1010 VOLUME 60 NUMBER 6 JUNE

7 RADIOSURGERY OF ARTERIOVENOUS MALFORMATIONS TABLE 6. Radiosurgery of arteriovenous malformations: Results after a single treatment Series (ref. no.) No. of patients Obliteration (%) Complications (%) Fatal rebleeding (%) Bollet et al., 2004 (8) Pollock et al., 2003 (53) Friedman, 2002 (21) Inoue and Ohye, 2002 (29) Chang et al., 2000 (11) Touboul et al., 1998 (73) Sasaki et al., 1998 (60) Karlsson et al., 1997 (33) Colombo et al., 1994 (13) Kondziolka et al., 1993 (34) although further clinical testing is required to validate this observation. The improvement in neurodeficit observed in 44.6% of the affected patients was higher in younger patients with a history of previous hemorrhage, which could, therefore, be attributed to recovery from bleeding. Plasticity and recovery are higher in younger patients, as would be expected. Complications of Radiosurgery Complications after radiosurgery are manifested as acute, subacute, and delayed. Acute complications associated with the performance of the treatment itself are caused by occasional complications of cerebral angiography, which are part of the treatment procedure. These complications, represented by temporary vasospasm or headache, usually resolve within a few hours; morbidity from angiography in the hands of an experienced neuroradiologist is infrequent. Focused radiation to the AVM nidus can provoke epileptic seizures in some patients, usually within 24 hours of the treatment, especially in patients with a previous history of secondary epilepsy. In these cases, this acute toxic reaction to radiation can be decreased by the administration of corticoids and anticonvulsant drugs (34). Acute serious or permanent sequelae associated with the performance of the treatment itself have not been observed. Subacute complications are caused by postirradiation edema, which can be observed after a delay of several months, usually within 6 to 24 months, but most frequently within 1 year after radiosurgery. We have observed collateral edema less frequently in patients with a history of previous bleeding, surgery, or embolization. In these cases, there are usually changes observed on MRI scans before the treatment, which are probably not only edema but also represent gliosis after these events. These glial changes probably make the brain tissue around the AVM less susceptible to postirradiation edema induction or mask the subclinical appearance of collateral edema. The risk of collateral edema was also dependent on volume and marginal dose. This risk seemingly decreased for the highest volumes and highest marginal doses, but in the case of large volumes, the marginal dose was significantly reduced; vice versa, the highest marginal doses were only applied to the smallest AVMs. An abrupt hemodynamic change after microsurgery or embolization can cause vasomotor paralysis with edema and capillary hemorrhage around the AVM bed or an occlusive hyperemia from the sudden disruption of the venous drainage or retrograde thrombosis in interrupted feeding arteries (45, 65). Edema observed after radiosurgery occurs at a time when the AVM vessels show continual flow void and obliteration is not accomplished; thus, the reasons are not hemodynamic changes caused by obliteration but rather a toxic effect on the surrounding tissue or the AVM itself. The latter seems to be the more likely with the contribution of the endothelial vascular growth factor, whose presence in vessel malformations has been proven (59). The release of this factor into the surrounding brain tissue after radiation damage can lead to the edema induction in way similar to what has been observed in the case of brain tumors (7, 25, 31, 59, 69, 76). Delayed complications could appear many years after the treatment. Late cystic formation was reported 5 to 15 years after the treatment and could be detected in 1.6 to 3.4% of patients, although surgical intervention was only required in 0.2% of the reported patients (11, 30, 50, 53, 75). Bleeding after angiographic confirmation of obliteration was also reported in one out of a group of 100 patients (63). We have not observed this type of complication to date. We cannot exclude clinically silent late changes in the brain, but the risk of late symptomatic complications seems to be very low and per mil. We observed an organized hematoma with expansive behavior in one patient 33 months after radiosurgery, although an AVM was not detected by angiography. A similar complication was reported by Szeifert et al. (70). There is a small possibility that AVMs may reappear after having been totally occluded after radiosurgery (41). In some cases, AVMs have been reported as growing lesions reappearing even after total open resection (2). However, the recanalization of patients without hemorrhage was not observed; therefore, we have not found evidence that we should change our practice, in which only symptomatic patients are followed once complete obliteration has been verified by angiography. Additional examinations after obliteration do not need to be performed routinely (41). NEUROSURGERY VOLUME 60 NUMBER 6 JUNE

8 LIŠČÁK ET AL. The risk of complications after the first radiosurgery treatment was 8%; in the case of repeated radiosurgery treatment, this risk fell to 2.9%. We tended to reduce the marginal dose for repeated radiosurgery because of concerns for increased risk of complications, which have not been confirmed. Therefore, it does not seem to be necessary to reduce the dose for repeated radiosurgery, which is associated with an acceptable risk of 2 to 5% in other series (20, 44). On the contrary, because of the reduced volume, even higher marginal doses can be considered (20). In multi-institutional analysis of complication outcomes, the resolution of symptoms was greater in patients with no previous history of hemorrhage and in patients with symptoms of minimal severity (19). Risk of Rebleeding The morbidity and mortality from rebleeding reported as a complication of radiosurgery are questionable. Previous open surgery or embolization was performed in 35% of the patients in our series. Once the combined treatment was performed on the patient and rebleeding occurred, it was disputable that radiosurgery was responsible for this event. Thus, the risk of rebleeding during the latency period of the healing process after radiosurgery can be evaluated only in terms of the potential cure rate of alternative treatment methods. In the published microsurgical series, late effects are only evaluated in selected patients with radical AVM resection (28, 36). In these patients, the risk of rebleeding after partial resection or embolization of AVM is not known, although it is either lifelong or lasts until the curative treatment is performed (5). The natural course of the disease represents a risk of rebleeding of 2 to 4% annually with a 1% risk of mortality and a 2.7% combined risk of major morbidity and mortality annually for the patient (9, 49). In our series, the risk of bleeding was 2.5% annually before the treatment and 2.1% after radiosurgery, which is less but not significantly so. Although the percentage of patients with rebleeding after radiosurgery varies between 3.4 to 10% (11, 29, 30, 54, 60, 63, 73, 77), the number of fatal hemorrhages is reported between 0 to 3.5% (13, 21, 30, 53, 54, 60, 63). Rebleeding appeared in 19 (6.5%) of the patients in our series, three (1%) of whom died. Two of these patients were considered inoperable, and one patient underwent an open surgery before radiosurgery. Other patients with rebleeding also underwent embolization or a combination of embolization and surgery before the gamma knife treatment. It is apparent that rebleeding is not associated with the treatment itself; otherwise one event (rebleeding) should be considered as complication of many treatments (open surgery, embolization, or radiosurgery) in some patients. Evaluation of Radiosurgery in the Management of AVMs Intracerebral AVMs most frequently manifest through bleeding, which is the most dangerous manifestation of the disease for the patient (9, 10, 49). Therefore, the risk of morbidity and mortality from bleeding is the major reason for active treatment of AVMs (60). The risk posed by leaving the disease to its natural course is weighed against the risk of treatment, which leads to the acceptance of a higher risk in younger patients and a more conservative approach in the older patients (4). The risk of bleeding through leaving the disease to take its natural course can be estimated by the formula suggested by Kondziolka et al. (35). When we consider that the annual risk of mortality is 1% in untreated AVMs (3) and that the cumulative risk of morbidity from radiosurgery was 3.4% in our series, the indications for gamma knife radiosurgery are justifiable for patients up to the age of 85 years. Only radical resection or embolization can provide immediate treatment effects for AVMs. Unfortunately, only rarely does embolization lead to the complete obliteration of an AVM; therefore, the embolization is not curative for the most part but is used only as an adjuvant treatment before microsurgery or radiosurgery (4, 5, 23, 24, 37, 74). In a recently published series, complications were not infrequent in embolized patients, and permanent morbidity or mortality could be observed in 11% of embolized patients (71). Therefore, embolization is not recommended as the first treatment choice for AVMs when radiosurgery or microsurgery can be performed alone (15). Preoperative embolization should be used more thoughtfully and critically than as currently practiced (27). Open resection of an AVM offers the patient a cure by radical removal, which is achieved with considerably low morbidity and mortality in many centers (6, 38, 48, 51, 61, 72). However, if the localization of an AVM is in eloquent or deep brain structures, microsurgical resection could lead to high morbidity and mortality (46) and radical resection, which is mandatory to prevent rebleeding, cannot be achieved in every case. Resection of AVMs in deep structures with no neurological deficit before the treatment can lead to deterioration of the quality of life and must, therefore, be carefully assessed (60), especially in patients with no history of bleeding (40). However, comparison of the mortality associated with open surgery and radiosurgery seems to be problematic. Mortality in open surgery is influenced by the fact that patients could undergo operation for acute hemorrhage in a deteriorated condition as a salvage treatment. Radiosurgery as an elective procedure handles patients in a stabilized condition when, in cases of previous hemorrhage, the hematoma has been reabsorbed. Significant numbers of patients referred for radiosurgery are considered to be inoperable; thus, the characteristics of the patients treated by open surgery and radiosurgery differ widely. Radiosurgery of AVMs is usually recommended in cases in which safe and radical open surgery cannot be performed or as a choice of the patient. The major limitation for AVM radiosurgery in the referred period was the volume of the nidus. Staged radiosurgery (i.e., treating only part of the lesion at each stage, usually with a 3 6 mo interval) for higher volume AVMs began at our center in the second half of Staged radiosurgery proved to be a valuable treatment option (17, 56) and is currently considered for larger AVMs when previous embolization or microsurgery failed or were not indicated. After incomplete obliteration of the AVM, it is also possible to perform open surgery (66). Multimodal treatment (radio VOLUME 60 NUMBER 6 JUNE

9 RADIOSURGERY OF ARTERIOVENOUS MALFORMATIONS surgery, microsurgery, and embolization) allows some complex cases to be cured successfully (14, 39, 60, 66). Conventional fractionated radiotherapy has a lower chance of being curative because AVMs comprise late responding tissue with a low α-to-β ratio. The cure rate after conventional radiation therapy was proven disappointing and was reported to be about 20% (58). A similar cure rate, 15.9%, was also observed after stereotactic proton beam radiosurgery (62). CONCLUSION Gamma knife radiosurgery can offer obliteration to more than 90% of treated AVM patients with a low risk of morbidity, even in case of repeated treatment. The chance for obliteration was higher for smaller volume AVMs and higher doses applied. The risk of morbidity and mortality from rebleeding during the latent period after radiosurgery also covers patients with previous incomplete microsurgery or embolization. Therefore, risks of treatment procedure and rebleeding after the treatment should be recognized in all treatment methods. REFERENCES 1. Andrade-Souza YM, Zadeh G, Ramani M, Scora D, Tsao MN, Schwartz ML: Testing the radiosurgery-based arteriovenous malformation score and the modified Spetzler-Martin grading system to predict radiosurgical outcome. J Neurosurg 103: , Akimoto H, Komatsu K, Kubota Y: Symptomatic de novo arteriovenous malformation appearing 17 years after the resection of two other arteriovenous malformations in childhood: Case report. Neurosurgery 52: , Al-Shahi R, Warlow C: A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain 124: , Auger RG, Wiebers DO: Management of unruptured intracranial arteriovenous malformations: A decision analysis. Neurosurgery 30: , Benati A: Interventional neuroradiology for the treatment of inaccessible arterio-venous malformations. 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10 LIŠČÁK ET AL. 35. Kondziolka D, McLaughin MR, Kestle JRW: Simple risk predictions for arteriovenous malformation hemorrhage. Neurosurgery 37: , Korosue K, Heros RC: Complications of complete surgical resection of AVMs of the brain, in Barrow DL (ed): Intracranial Vascular Malformation. Rolling Meadows, AANS, 1990, pp Krajina A, Náhlovský J, Malec R, Nemecková J, Parízek J, Rehák S, Drahokoupilová H, Látr I, Kaltofen K, Šercl M, Kroó M, Bašta V, Krajícková D: Embolization in the treatment of arteriovenous malformations [in Czech]. Ces a Slov Neurol Neurochir 93: , Lawton MT; UCSF Brain Arteriovenous Malformation Study Project: Spetzler- Martin Grade III arteriovenous malformations: Surgical results and a modification of the grading scale. Neurosurgery 52: , Lawton MT, Hamilton MG, Spetzler RF: Multimodality treatment of deep arteriovenous malformations: Thalamus, basal ganglia, and brain stem. 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11 RADIOSURGERY OF ARTERIOVENOUS MALFORMATIONS COMMENTS The authors provide a thoughtful and detailed analysis of a large cohort of patients who received radiosurgery for arteriovenous malformation (AVM) at Na Homolce Hospital in between 1992 and Overall, the findings of this study are similar to those of earlier reports with respect to factors associated with obliteration (AVM volume, radiation dose, and Spetzler-Martin grade), edema (age and radiation dose), and morbidity (AVM volume). Not typically analyzed in radiosurgical studies is the probability of neurological improvement after radiosurgery; in the current series, patients younger than 25 years old and those with a previous hemorrhage were most likely to show some recovery of function. The finding of neurological improvement in patients with previous bleeding likely relates to the timing of the radiosurgery in relation to the hemorrhage. Of patients who undergo radiosurgery soon after a hemorrhage occurs, many will improve because the hematoma is absorbed and functional independence can therefore be regained (1). Stated another way, results are generally better in situations where the prognosis of the disorder, when left untreated, is favorable. Unquestionably, the strength of this report is the completeness of the authors angiographic follow-up examinations after the AVM radiosurgeries. Whereas most studies report that 60 to 70% of patients participate in angiographic follow-up, this group was able to perform angiography on an annual basis for 90% of the patient population. Using a worst-to-best case scenario to account for the small number of patients not having angiography after radiosurgery, 4 years after the first procedure, the chance of AVM obliteration was between 74 and 83%, and 4 years after patients received repeat radiosurgery, the chance of AVM obliteration was between 69 and 84%. At 7 years after the first procedure, the cumulative incidence of AVM obliteration after one or more radiosurgical procedures exceeded 90% via actuarial methodology. Despite the exceptional angiographic information provided, the median follow-up period after radiosurgery was only 38 months and is, therefore, inadequate to account for late complications that are known to occur after AVM radiosurgery. In our analysis of patients undergoing AVM radiosurgery between 1990 and 1997, 3% had late complications that required additional treatment (2). The median time to the onset of these delayed problems was 65 months. Complications included cyst formation and persistent edema, which usually requires resection of the obliterated nidus. Nonetheless, this is a landmark report on AVM radiosurgery that will be repeatedly referenced in the upcoming decades. Bruce E. Pollock Rochester, Minnesota 1. Hartmann A, Mast H, Mohr JP, Koennecke HC, Osipov A, Pile-Spellman J, Duong DH, Young WL: Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke 29: , Pollock BE, Gorman DA, Coffey RJ: Patient outcomes after arteriovenous malformation radiosurgical management: Results based on a 5- to 14-year follow-up study. Neurosurgery 52: , The investigators of the Prague center provide a comprehensive outcome analysis related to their experience with AVMs. The strengths in this single-center report are that the authors have great experience and the opportunity to intensively study their patient population in the Czech Republic (perhaps their patients are not as mobile as patients in the United States). The results are excellent. This report reemphasizes that more than one radiosurgical procedure may be required to achieve the desired final result, which is complete AVM obliteration. Data from both our center and the University of Tokyo suggest that complete AVM obliteration as defined by angiography is an important indicator of success, but the lifetime risk of hemorrhage is still not zero because of recanalization, inadequate imaging, or bleeding from a vascularized gliotic scar. Late complications such as cyst formation seem to be unusual in this series; the incidence of 1 to 3% seems high to us as well. Perhaps this is related to our relatively recent ability to perform more conformal and selective plans on the basis of three-dimensional imaging with magnetic resonance imaging scans and digital subtraction angiography, with the delivery of less radiation to adjacent tissue. We have found that estimating the volume of brain receiving greater than 12 Gy of radiation helps to predict the risk of even temporary magnetic resonance imaging scan changes of edema. Of course, understanding the real estate of the AVM is critical to the prediction of complication risk. Embolization before radiosurgery did not seem to affect the results in this group s experience; perhaps they only treated the previously embolized volume. Better consultation between endovascular, radiosurgical, and microsurgical specialists may result in better-informed patients. L. Dade Lunsford Pittsburgh, Pennsylvania This study by Liščák et al. provides a very good retrospective clinical evaluation of radiosurgery for AVM. Although much has been written regarding AVM, in fact, few previous series have reported such a high rate of long-term follow-up. The safety and efficacy of radiosurgery is confirmed, and predictive factors are discussed. In this series of 330 retrospectively analyzed patients, follow-up data are available for 90% of the treatments, including 23% of patients who were treated twice. The results of this group s long-term follow-up indicate overall low risks of mortality (1%, caused by rebleeding) and morbidity (3.4%, including rebleeding) for gamma knife surgery to treat AVM. Moreover, Liščák et al. demonstrate the high rate of efficacy of radiosurgery for AVM, with a cure rate of 92%. Interestingly, longterm symptomatic complications (late cystic formation) were not observed in the Prague patients treated in the era of modern imaging. Liščák et al. report a series of only 330 consecutive AVMs treated between 1992 and 2000, which represents just 10% of their overall radiosurgical activity. This is in contrast with the situation in Europe and the Middle East, where AVMs globally represent 22% of the total indication for gamma knife surgery. Previously, open surgery or embolization was performed in only 35% of patients with AVM. Conversely, the small median AVM nidus volume (3.9 cm 3 ) in this series is also related to the authors specific strategy for treating very large AVMs. As explained in the Discussion, until 2000, the authors policy for gamma knife indication for AVM was to reject large lesions (staged treatment for large AVMs began in Prague only during the second half of 2000), which perhaps explains the specificities of this series. In line with previous reports, the chance of AVM obliteration was higher for smaller-volume AVMs and those who received higher applied doses of radiation. However, the analysis of prognostic factors by Liščák et al. sometimes seems paradoxical. For example, morbidity is higher in patients with small AVMs and lower in patients undergoing retreatment! The authors explain this observation by noting that a lower radiation dose is used to treat large AVMs and to perform retreatments. However, because their overall morbidity is extremely low, we suspect this reduction was somewhat exaggerated for the large AVM and retreatment cases. Liščák et al. thus provide us with very useful data for the decision-making process regarding small- or middle-sized AVMs. If the major limitation of radiosurgery remains the bleeding risk during the latent period, then the overall morbidity of rebleeding NEUROSURGERY VOLUME 60 NUMBER 6 JUNE

12 LIŠČÁK ET AL. is 6.8% as it relates to radiosurgery itself (3.4%) or rebleeding (3.4%), including a 1% mortality risk. Microsurgery or embolization is a more suitable alternative treatment when it can provide the patient with an overall lower chance of morbidity. However, Liščák et al. are correct to insist that at the time of evaluation of alternative techniques, not only the risks of a treatment procedure but also the rebleeding risk after open surgery or embolization treatment should be recognized and taken into account. Manabu Tamura Jean Régis Marseille, France Liščák et al. present data regarding the rate of cure of AVMs treated with gamma knife radiosurgery during a period of 8 years at one hospital. During this time, 330 patients underwent radiosurgery. Of these, approximately 9 of 10 patients were available for follow-up. The authors realized complete AVM obliteration via conventional angiography in 74% of the patients after one treatment of radiosurgery. If a cure was not confirmed within 3 years of the first treatment, patients underwent a second round of treatment, usually at a slightly lower radiation dose. Of those undergoing a second radiosurgery, 69% of patients achieved a cure, which led to an overall cure rate of 92% for the entire group. The authors note that the risk of rebleeding after radiosurgery was 2.1% until AVM obliteration, and the cumulative risk of morbidity from radiosurgery was 3.4%. An important aspect of this research that is missing is standardizedoutcome data. Although we are given a litany of statistics regarding the rates of AVM obliteration, neurodeficit, edema, seizures, Spetzler-Martin grade, and mortality, we are not provided with outcome descriptions in terms of the Modified Rankin Scale, a Glasgow Outcome score, or the like. Ultimately, a positive patient outcome, and not angiographic obliteration, is the goal of any treatment for AVMs. Yet, these data seem to confirm previous reports that radiosurgery is a viable treatment option for cerebral AVMs. The authors suggest that many of their patients had been deemed inoperable, but, in fact, 89% of their patients were Spetzler-Martin grades I to III, and the vast majority were supratentorial. These lesions, of course, are also the kind that are best treated with microsurgery at a comprehensive cerebrovascular center. As the authors point out, comparisons between radiosurgery and microsurgery are difficult on the basis of data such as theirs. Judgments on the basis of this type of research are inevitable, however, and we must continue to compare results of any treatment to the time-tested and durable results of microsurgery that are reported in the literature. In general, optimal management decisions and strategies are facilitated by multidisciplinary teams that include vascular neurosurgeons, endovascular surgeons, and radiosurgeons. Well-thought-out strategies prevent overlapping or duplicative treatment actions, such as embolizing a small, deep AVM that is best suited for radiosurgery. Edward Duckworth H. Hunt Batjer Chicago, Illinois Liščák et al. have admirably performed angiographic follow-up on approximately 90% of the 330 patients who were treated with gamma knife stereotactic radiosurgery at their center. The authors found that 222 (67%) of 330 patients experienced AVM obliteration after the first round of radiosurgery. These results are similar to previously reported outcomes. However, the authors claim an overall 92% AVM obliteration rate by offering patients a second round of stereotactic radiosurgery in cases in which the AVM was not obliterated 3 years after the first round of radiosurgery. Of note, they included as cured some rare cases in which early venous drainage was still observed angiographically. The authors analyzed factors that may play a role in obliteration of the AVM. Not surprisingly, they found that smaller AVMs and higher radiation doses were associated with AVM obliteration. When the first round of radiosurgery was not successful, it was recognized that it nonetheless reduced the nidus for the second round of treatment. With a smaller nidus, the authors elected to use a reduced radiation dose for patients who underwent a second round of radiosurgery. The reduced dosage likely led to a reduced rate of complications after the second treatment. The authors additionally analyzed their data and looked at other outcomes besides AVM obliteration. They noted no significant difference in the rate of hemorrhage before and after treatment, and that approximately 40% of the patients with a neurodeficit attributable to the AVM actually improved after stereotactic radiosurgery. Additionally, approximately 40% of the patients with seizures had improvement in seizure frequency after radiosurgery. The authors results of AVM obliteration agree with previously reported outcomes, and this report confirms that radiosurgery is an effective treatment for properly selected patients. This study also demonstrates that a second round of radiosurgery can be used safely to increase the obliteration rate if the first treatment does not cure the AVM. Additionally, this report also thoughtfully follows other patient outcomes besides obliteration of the AVM. These other outcomes can be very important when making a decision regarding which modality of treatment is best. Although radiosurgery is an important treatment modality for patients with AVMs, these patients should still be evaluated and treated in a center that has a multimodality team in place. Gordon T. Sakamoto Gary K. Steinberg Stanford, California 1016 VOLUME 60 NUMBER 6 JUNE