Cerebral arteriovenous malformations (AVMs) are. Seizure outcomes following radiosurgery for cerebral arteriovenous malformations

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1 Neurosurg Focus 37 (3):E17, 2014 AANS, 2014 Seizure outcomes following radiosurgery for cerebral arteriovenous malformations Ching-Jen Chen, M.D., 1 Srinivas Chivukula, M.D., 2 Dale Ding, M.D., 1 Robert M. Starke, M.D., M.Sc., 1 Cheng-Chia Lee, M.D., 1,3 Chun-Po Yen, M.D., 1 Zhiyuan Xu, M.D., 1 and Jason P. Sheehan, M.D., Ph.D. 1,4 1 Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia; 2 Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 3 Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; and 4 Department of Radiation Oncology, University of Virginia Health System, Charlottesville, Virginia Object. Seizures are a common presentation of cerebral arteriovenous malformations (AVMs). The authors evaluated the efficacy of stereotactic radiosurgery (SRS) for the management of seizures associated with AVMs and identified factors influencing seizure outcomes following SRS for AVMs. Methods. A systematic literature review was performed using PubMed. Studies selected for review were published in English, included at least 5 patients with both cerebral AVMs and presenting seizures treated with SRS, and provided post-srs outcome data regarding obliteration of AVMs and/or seizures. Demographic, radiosurgical, radiological, and seizure outcome data were extracted and analyzed. All seizure outcomes were categorized as follows: 1) seizure free, 2) seizure improvement, 3) seizure unchanged, and 4) seizure worsened. Systematic statistical analysis was conducted to assess the effect of post-srs AVM obliteration on seizure outcome. Results. Nineteen case series with a total of 3971 AVM patients were included for analysis. Of these, 28% of patients presented with seizures, and data for 997 patients with available seizure outcome data who met the inclusion criteria were evaluated. Of these, 437 (43.8%) patients achieved seizure-free status after SRS, and 530 (68.7%) of 771 patients with available data achieved seizure control (seizure freedom or seizure improvement) following SRS. Factors associated with improved seizure outcomes following SRS for AVMs were analyzed in 9 studies. Seizurefree status was achieved in 82% and 41.0% of patients with complete and incomplete AVM obliteration, respectively. Complete AVM obliteration offered superior seizure-free rates compared with incomplete AVM obliteration (OR 6.13; 95% CI ; p = ). Conclusions. Stereotactic radiosurgery offers favorable seizure outcomes for AVM patients presenting with seizures. Improved seizure control is significantly more likely with complete AVM obliteration. ( Key Words arteriovenous malformation seizure epilepsy stereotactic radiosurgery review Cerebral arteriovenous malformations (AVMs) are congenital vascular anomalies that have an estimated incidence of approximately 1 in 100,000 persons. 3,9,30,35 Patients often present by the 3rd decade of life with hemorrhage, seizure, or neurological deficit. 8,50 The most common presentation in patients harboring such vascular anomalies is hemorrhage, with the estimated risks ranging from 2% to 4% annually. 11,27 Due to the significant morbidity and mortality associated with AVM rupture, the majority of AVM treatments and studies have focused on its natural incidence and the prevention of its Abbreviations used in this paper: AED = antiepileptic drug; AVM = arteriovenous malformation; GKRS = Gamma Knife radiosurgery; PBT = proton-beam therapy; SRS = stereotactic radiosurgery. Neurosurg Focus / Volume 37 / September 2014 occurrence. 25 In contrast, less attention has been given to seizures in patients with AVMs. Seizures occur in up to 57% of patients with cerebral AVMs. 46 Among patients with unruptured AVMs, seizures are the most common clinical presentation. 13 Despite antiepileptic drug (AED) therapy, seizure response remains variable for these patients. 14,51,65 As disabling seizures can have detrimental effects on patients quality of life, reduction or elimination of seizures is crucial in the optimal management of these patients. Stereotactic radiosurgery (SRS) is a frequently employed modality for the treatment of AVMs; it offers a minimally invasive method of achieving AVM obliteration with rates that vary widely depending on multiple factors, including nidus volume, venous drainage pattern, prior embolization, and radiosurgical margin dose. 13,42,47,59 1

2 C. J. Chen et al. To date, the goal of SRS in AVM treatment has been to eliminate the risk of hemorrhage by achieving complete obliteration of the nidus. 13 However, the indications for SRS in the management of seizures associated with AVMs are not well defined, with relatively few studies investigating seizure outcomes following SRS. 5,69 To evaluate the efficacy of SRS for the treatment of AVM-related seizures and identify factors associated with improved post-srs seizure control, we performed a systematic review of the available literature regarding AVM seizure outcomes following SRS. Methods Inclusion Criteria Inclusion criteria for the studies were defined in an attempt to ensure a balance between a relatively homogeneous and the largest possible patient population. The following criteria were devised for inclusion in the final analysis: 1) the study must contain at least 5 patients with both an AVM and presenting seizures that were treated with SRS; 2) the study must include vascular malformations that were AVMs; 3) the study data must include post-srs outcome data regarding AVM obliteration and/ or seizures; and 4) the language of the study must be in English. Case series consisting of fewer than 5 patients, studies pertaining to dural arteriovenous fistulas or cerebrovascular lesions other than AVMs (i.e., cavernous malformations), and studies in languages other than English were excluded from this analysis. Literature Search A systematic literature review was performed using PubMed. The literature search was performed using PubMed with the search term: seizure OR epilepsy AND arteriovenous malformation AND radiosurgery. The search included articles published from 1987 through The search yielded 198 articles, which were then screened by title and abstract. Twenty-two articles were selected from the initial screening process and were subject to further detailed reviewed for relevance and usable data matching our inclusion criteria. Of these, 3 studies were excluded for reasons including lack of or insufficient reported seizure outcomes and overlapping published patient data from the same institution in a more recent study. For the final quantitative analysis, we identified 19 series comprising 1104 patients with AVMs and seizures who underwent SRS. 2,13,16,20,22,33,34,37,39,41,43,48,57,58,63,64,69,71,73 Figure 1 shows a flow chart of the review process. Fig. 1. Flow chart illustrating the systematic review process. The initial PubMed search yielded 198 articles; 22 articles were selected from the initial screening process, and these were further reviewed for relevance and usable data matching the inclusion criteria. Three studies were excluded for reasons including no or insufficient seizure outcomes reported and overlapping of published patient data from the same institution in a more recent study. In 19 case series with 3971 AVM patients treated with SRS, 1104 patients had concurrent seizures. Of these, 997 patients with radiological and/or clinical follow-up were included in this analysis. Literature Review and Data Extraction Demographic, radiosurgical, clinical, and radiological outcomes data were extracted from studies that met the inclusion criteria. Demographic data included the number of patients treated and the mean age and sex of all patients reported in each study, as well as those presenting with seizures. Other data obtained included Spetzler-Martin grade and history of AVM rupture. 60 For patients with AVMs and seizures, follow-up duration and history of prior microsurgical resection and embolization were also recorded. For studies that distinguished patients with seizures following hemorrhage from those with hemorrhage-independent seizures, only data from patients with hemorrhage-independent seizures were included for analysis. Radiosurgical data reviewed included the type of SRS used (i.e., Gamma Knife radiosurgery [GKRS], proton-beam therapy [PBT], and LINAC-based radiosurgery) and treatment parameters when available. Data regarding seizure outcomes were also reviewed; all seizure outcomes were categorized into 4 groups as follows: 1) seizure free, 2) seizure improvement (decreased seizure frequency without seizure freedom), 3) seizure unchanged, and 4) seizure worsened. When available, the Engel Seizure Outcome Scale following SRS was noted. 18 For studies in which only the Engel classification was reported, Class I was designated seizure free, Classes II and III were designated seizure improvement, and Class IV was reported as seizure unchanged. For the purpose of this review, the term seizure control encompassed Engel Classes I III (patients who achieved seizure-free status and those with seizure improvement). For those with seizure-free status and/or seizure improvement, patients off AEDs following SRS were recorded 2 Neurosurg Focus / Volume 37 / September 2014

3 Radiosurgery for AVMs: seizure outcomes when available. Rates of AVM obliteration were evaluated independently in each study by using a combination of angiography and MRI. Incomplete AVM obliteration included subtotal, partial, and no AVM obliteration. Factors associated with favorable seizure outcomes (seizurefree or seizure-control outcomes) following SRS were also noted. Statistical Analysis All statistical analyses were performed using Review Manager (RevMan) version (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). Seizure outcome data were extracted for patients with and without complete AVM obliteration from each study with available data. The Mantel-Haenszel test was used to compute the odds ratio. Under the assumption of possible clinical diversity and methodological variation between studies, the random-effects model was used and presented in this study. Study heterogeneity was detected using the chi-square and I 2 test statistics. However, because the chi-square test lacks power when the number of studies is small, significant heterogeneity was considered to be present when both the chi-square value was within the 10% level of significance (p < 0.10) and the I 2 value exceeded 50%. Possible reasons for variation across studies are addressed in the limitations section of this review. All statistical tests were 2-sided, and p < 0.05 was considered statistically significant. Results AVM Radiosurgery Series Included for Analysis Nineteen case series dating from 1991 to 2013 met the inclusion criteria; these studies contained 3971 AVM patients who were treated with SRS. Of these, 1104 (27.8%) patients presented with seizures; 997 of 1104 patients (90.3%) had radiological and/or clinical follow-up. The SRS modalities used in these studies included GKRS, LINAC, and PBT in 12, 4, and 2 series, respectively; 1 study used both GKRS and LINAC. Follow-up intervals ranged from 14 to 93 months. Table 1 summarizes the case series included in this review. Neurosurg Focus / Volume 37 / September 2014 Seizure Outcome After SRS Of the 997 patients with available follow-up, 437 (43.8%) patients achieved seizure-free status following SRS. In the 8 studies with reported AED use, 106 (53.5%) of 198 seizure-free patients were no longer being treated with AEDs at last follow-up. For 5 studies, only seizurefree outcomes were reported. Of the remaining 14 studies in which seizure improvement was reported, there were 771 patients with available follow-up, comprising 228 (29.6%) with seizure freedom and 242 (31.4%) with decreased seizure frequency, for a seizure control rate of 68.7%. Seizure status was unchanged in 210 (28.4%) of 739 patients in 13 studies with available data and worse in 20 (4.0%) of 494 patients in 8 studies. Table 1 shows seizure outcomes following SRS for AVMs in the included studies. When studies were analyzed using respective seizure-free and seizure improvement percentages, the mean seizure-free rate was 53.4% (95% CI 39.6% 67.1%), and the mean seizure improvement rate was 26.6% (95% CI 15.2% 37.9%). A mean overall seizure control rate of 76.2% (95% CI 67.0% 85.3%) was achieved. The mean follow-up time for these studies was 45.6 months (range months). However, for the few studies in which these data were reported, the time to achieving seizurefree outcome ranged from less than 3 months to 20.5 months. Obliteration and Other Factors Related to Seizure Outcome Among the 9 studies with available radiological outcomes, complete AVM obliteration was achieved in 237 of 401 patients (59.1%, 95% CI 51.4% 66.8%). Seizure-free status was achieved in 176 of 215 patients with complete AVM obliteration (81.9%) in the 8 studies with available data, whereas seizure-free status was obtained in 59 of 144 patients with incomplete AVM obliteration (41.0%) in 7 studies with available data. Analysis of pooled data from the 7 studies with seizure-free outcomes for both complete and incomplete AVM obliteration demonstrated that complete obliteration offered superior seizure-free rates (OR 6.13; 95% CI ; p = ). The analysis also demonstrated significant heterogeneity among the included studies (chi-square = 20.14; p = 0.003; I 2 = 70%). Results of the analysis are summarized in Fig. 2. Factors associated with seizure outcomes following SRS for AVMs were analyzed in 9 studies and are summarized in Table 2. AVM obliteration was found to be significantly associated with improved seizure control in four studies. 33,41,69,71 However, this association was found to be nonsignificant in 4 other studies. 22,37,39,57 Relationships between seizure characteristics and seizure outcomes following SRS were also inconsistent; complex partial seizures with or without secondary generalization, generalized tonic-clonic seizures, infrequent and shortduration seizures, and seizure frequency have been associated with improved seizure control. 16,33,39,57,71 In contrast, other studies have also found no significant relationship between seizure outcome and seizure type, duration, frequency, and pattern or age at seizure onset. 16,37,39,57,71 The influence of hemorrhage on seizure outcome was also controversial. Two of the 3 studies that evaluated radiosurgery margin and/or maximum dose showed no significant association between these radiosurgical parameters and seizure outcome. 39,57 Although in some studies an association was observed between improved seizure control and AVM location and size, many studies found no such association between seizure outcome and AVM characteristics (volume, size, drainage, location, and Spetzler- Martin grade). Patient age and sex were consistently not associated with seizure outcome. Discussion Approximately one-third of patients harboring AVMs present with seizures. 16,21,43,73 In this systematic review, we observed an overall seizure incidence of 28% in studies that included AVM patients treated with SRS. Risk factors 3

4 C. J. Chen et al. TABLE 1: Summary of SRS series and outcomes for patients with seizures and AVMs Authors & Year Overall w/ Seizures w/ Follow-Up No. of Patients Seizure Status After SRS (no. of patients) Follow-Up (mos) Treatment Modality No. of Patients w/ Complete AVM Obliteration/No. w/ AVMs Seizure Free Improvement Unchanged Worsened Lunsford et al., GKRS Steiner et al., GKRS Sutcliffe et al., GKRS Gerszten et al., GKRS Eisenschenk et al., LINAC 9/ Kurita et al., GKRS 21/ Kida et al., GKRS 22/ Hoh et al., PBT 68/ Nataf et al., LINAC 4/6 4 Schäuble et al., GKRS 26 Silander et al., PBT Andrade-Souza et al., LINAC 15/ Lim et al., GKRS 16/ Zeiler et al., GKRS Hyun et al., GKRS 33 Yang et al., GKRS 60/86 66 Ding et al., GKRS Fokas et al., LINAC Wang et al., GKRS/LINAC 22/33 20 total / (43.8%) 242 (32.7%) 210 (28.4%) 20 (4.0%) 4 Neurosurg Focus / Volume 37 / September 2014

5 Radiosurgery for AVMs: seizure outcomes Fig. 2. Forest plot of the odds ratio of seizure-free outcomes for patients with complete and incomplete AVM obliteration. The estimated odds ratio and 95% CI of each included study is represented by the center of the squares and the horizontal line, respectively. The summary odds ratio and 95% CI are shown in bold and are represented by the black diamond. Tests of heterogeneity and overall effect are given below the summary statistics. M-H = Mantel-Haenszel; Oblit. = obliteration. for seizure presentation in these patients have been previously documented and include younger age, male sex, lobar or cortical AVM location, and large AVM size. 12,21,23, 33,40,44,46,52,61,67,68 Other AVM characteristics associated with seizures, such as frontal or temporal topography, superficial venous drainage, and arterial border-zone AVM location, have also been reported. 21,23,33,40,52,62,68 While defining factors for seizure development in patients with AVMs may be important for risk stratification, analyzing seizure outcome following AVM treatment will help direct future therapy. Although seizures are the second most common presentation in patients with AVMs, seizure control has not been the primary objective of AVM treatment. 31 Current treatment options for patients with AVMs include microsurgery, embolization, and SRS. Of these, SRS has become an increasingly popular therapeutic modality. This systematic review evaluated the efficacy of SRS in treating patients with AVM-associated seizures in 19 studies. The seizure-free rates following SRS varied widely, ranging from 0% to 95%, with a mean of seizure-free rate of 53.4% in the 19 identified studies. In addition, approximately half of the seizure-free patients were weaned off of AEDs after SRS. After a 2-year seizure-free status, there is general consensus for a slow withdrawal of AEDs, but the interval to freedom from AEDs was reported in only 1 study. 39,41,71 Yang et al. observed a median time of 4 years (95% CI years) to achieving AED cessation following SRS. 71 SRS seems to offer reasonable seizure-control TABLE 2: Factors associated with seizure outcomes following SRS observed in different studies Authors & Year Factors Associated w/ Improved Seizure Outcomes Factors Not Associated w/ Improved Seizure Outcomes Gerszten et al., 1996 Eisenschenk et al., 1998 Kurita et al., 1998 Kida et al., 2000 Hoh et al., 2002 Schäuble et al., 2004 no hemorrhage, higher-grade AVM complex partial seizure w/ or w/o secondary generalization, generalized tonic-clonic seizure w/o preceding partial seizures, AVM located in centrum or frontal regions infrequent seizures prior to SRS, short duration ( 6 mos) of seizure history AVM obliteration seizure as initial symptom (compared to following hemorrhage), radiosurgery margin dose <20 Gy short seizure history, association of seizure w/ intracranial hem- age & sex, AVM size orrhage, generalized tonic-clonic seizure type, deep/posterior fossa AVM location, AVM obliteration low seizure frequency score before SRS, small diameter/size of AVM, generalized tonic-clonic seizures simple partial seizure (unfavorable), AVM in temporal lobe exclusively or contiguous to temporal lobe (unfavorable), AVM size age & sex; seizure type & age at seizure onset; AVM side, location, drainage, nidus diameter, nidus vol; radiosurgery central & margin dose; AVM obliteration AVM size, AVM obliteration, seizure pattern risk factors for epilepsy (prior hemorrhage & partial resection), AVM Spetzler-Martin grade, duration of seizures, margin & max dose, AVM obliteration Lim et al., 2006 AVM obliteration AVM vol; seizure frequency & duration Yang et al., 2012 AVM obliteration seizure frequency score before radiosurgery AVM Spetzler-Martin grade, age at 1st seizure, duration of epilepsy before SRS, principal seizure type, embolization before SRS, post-srs imaging changes Wang et al., 2013 AVM obliteration prior embolization Neurosurg Focus / Volume 37 / September

6 C. J. Chen et al. rates, ranging from 50.5% to 100%, with a mean of 76.2%. Although SRS does not necessarily afford seizure-free status even with complete AVM obliteration, SRS provides an alternative treatment for lesions involving eloquent areas or those not amenable to microsurgery or embolization alone. The variability in seizure response following SRS may also be attributed to the stringency of follow-up evaluations, the subjective interpretations of seizure outcomes in retrospective series, and baseline differences in patient and AVM characteristics. Pathophysiology of Seizures Associated With AVMs The mechanisms of epileptogenesis secondary to AVMs remain unclear. Several authors have proposed mechanisms offering explanations for the pathophysiology of AVM-related seizures. Secondary epileptogenesis and the kindling phenomenon have been hypothesized by Yeh and Privitera; although not well studied in humans, these mechanisms have been observed in experimental animal studies. 24,45,72 Secondary epileptogenesis is caused by distant independent seizure foci believed to induce seizures through progressive signal amplification in response to low-intensity and initially ineffective electrical discharges in the brain. 17,72 Thus, concurrent treatment of cerebral AVMs along with adjacent or remote epileptogenic foci has been proposed. 72 Wolf et al. have suggested that a disturbed balance in the perilesional cortex between excitatory and inhibitory synaptic transmissions might contribute to epileptogenesis. 70 Immunohistochemically, they observed distinct differences in the distribution of neurotransmitter receptors between the perilesional zone and the normal cortex in surgical specimens from patients with neocortical epilepsy-associated lesions. 70 Kraemer and Awad hypothesized that neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology may all have roles in the pathogenesis of seizures. 38 Alterations in blood flow and the vascular steal phenomenon have also been proposed as mechanisms through which AVMs induce seizures. 4,6,7 The vascular steal phenomenon is thought to induce focal ischemia and hypometabolism, compromising cerebral oxygen extraction and glucose metabolism in the adjacent cortex. 4,38 Neuronal cell death, gliosis, functional compromise, and epileptogenesis in the adjacent cortex are possible consequences of ischemia. 38 Nonlethal ischemia may serve to promote microenvironments vulnerable to additional insults, such as hemosiderin deposition, thereby precipitating seizure development. 37,38 The mechanism by which ionizing radiation might affect epileptogenesis is not completely understood. Some investigators have proposed that the therapeutic effects of radiation treatment are on tissues surrounding the AVM, independent of radiation-induced AVM occlusion. 22,28,41 At nonnecrotizing radiation doses, seizure suppression may be attributable to neuromodulatory effects. 10,16,53,54 Inhibition of protein synthesis has been hypothesized as a downstream effect of irradiation, curtailing sustained spontaneous neuronal discharges, along with inducing differential effects on the inhibitory g-aminobutyric acid and excitatory amino acid systems. 10,53,54 Stereotactic radiosurgery may also achieve seizure control through a radiosurgically induced gliotic capsule around the nidus. Thus, the role of SRS may be to modify the area adjacent to the AVM, suppressing its epileptogenic activity while preserving its functional role. 53,54 In contrast, other authors have hypothesized that its effects stem from the treatment of the AVM itself, reducing the vascular steal phenomenon and thus the ischemia in the surrounding tissue. 22,28,39,41 The findings of the current Radiosurgery or Open Surgery for Epilepsy (ROSE) trial, which is assessing the efficacy of radiosurgical treatment for mesial temporal lobe epilepsy, and the successful treatment of hypothalamic hamartoma-associated gelastic seizures with SRS underscore the profound improvements that can be achieved with SRS in patients with structural etiologies of epilepsy. 15,55 Relationship Between AVM Obliteration and Seizure Outcomes Following SRS Regardless of the mechanisms by which AVMs cause seizures, complete AVM obliteration following SRS appears to offer favorable seizure outcomes. 33,41,69,71 Our analysis, based on compiled data from 7 studies, demonstrated that seizure-free rates were significantly higher with complete AVM obliteration than with incomplete obliteration (81.9% vs 41%). The seizure-free rate for complete AVM obliteration is approximately twice that of the rate for incomplete AVM obliteration. However, it is also important to note that there were several studies in which such an association was not found. 22,37,39,57 Obliteration of the AVM is important for the reduction of future hemorrhage risk; however, some authors have suggested that it may not be required for seizure control. 26,32 Several studies have indicated that seizure frequency and intensity begin to decline several months following SRS and long before morphological changes or obliteration of the AVM, although higher seizure-free rates were observed in patients who achieved complete obliteration. 16,22,28,37,39,57,63,71 In a recent study of 86 patients with AVM-associated seizures treated with SRS, 24 (27.9%) patients were seizure free, with 19 achieving cessation of AEDs at 1-year follow-up, even though no patient had complete AVM obliteration. 71 These findings suggest that the mechanisms underlying reduction of seizure frequency and intensity following SRS may be 2-fold: 1) directly by restricting parenchymal epileptic activities in seizure foci and 2) indirectly by reducing blood flow through arteriovenous shunts even if the reduction in blood flow is only partial and not complete. 16,34,37,63 Other Factors Associated With Seizure Outcomes Factors associated with improved and worsened seizure outcomes following AVM SRS varied significantly across different series (Table 2). Seizure characteristics, such as complex partial seizures with or without secondary generalization, generalized tonic-clonic seizures, infrequent and short-duration seizures, and seizure frequency score were reported to be associated with favorable outcomes. 16,33,39,57,71 Kurita et al. did not observe associations between seizure outcomes and seizure type or 6 Neurosurg Focus / Volume 37 / September 2014

7 Radiosurgery for AVMs: seizure outcomes age at seizure onset. 39 The duration and frequency of seizures prior to SRS also did not demonstrate significant associations with seizure outcomes in studies by Lim et al. and Schäuble et al. 41,57 The association between radiosurgical parameters and seizure outcome was also unclear. Although the radiosurgery margin dose affected AVM obliteration rates, it did not seem to significantly influence seizure outcomes. 39,57 AVM characteristics also did not seem to have significant associations with post-srs seizure outcomes. 16,33,37,39,57,71 Overall, factors associated with seizure outcomes following SRS for AVMs are not as consistently identified as those related to obliteration. Future prospective studies with large cohorts are needed to further analyze potential predictors of seizure outcome that may be important for guiding overall AVM management and for patient counseling. Neurosurg Focus / Volume 37 / September 2014 Current Treatment Options for AVM Patients With Seizures Thus far, there have been no randomized clinical trials comparing seizure outcomes for different treatment modalities; conclusions have been based on analyses of retrospective studies. In a recent meta-analysis by Baranoski et al. comparing seizure outcomes among patients treated with microsurgical resection, SRS, and endovascular embolization, the authors found that microsurgical resection offered significantly higher seizure-free rates than SRS or embolization (seizure freedom rates of 78%, 63%, and 49% for surgery, SRS, and embolization, respectively). 5 Microsurgical resection also offered a significantly better seizure control rate than did SRS or embolization (90% vs 79% vs 66%, respectively) in the same study. However, when AVM obliteration was achieved, seizure-free outcome rates were significantly higher in patients treated with SRS than with microsurgical resection (85.2% vs 78.3%, respectively). 5 In a retrospective study evaluating seizure outcomes for microsurgery and SRS, Wang et al. found that in patients with pretreatment seizures microsurgery resulted in a higher seizure-free rate than SRS (58.8% vs 26.7%, respectively). 69 Furthermore, patients treated with microsurgical resection achieved sooner, if not immediate, seizure relief compared with patients treated with SRS, in whom seizure relief took as long as 20 months. 34 The majority of studies we reviewed, however, did not provide details regarding time to seizure control. Despite better seizure outcomes, microsurgical resection is associated with increased risk of new-onset seizures for patients without pretreatment seizures. 69 Surgical intervention may create new seizure foci and increase seizure frequency via cortical or subcortical damage from direct manipulation. Additionally, these surgically induced seizures may become progressively more intractable. 49,52,66 The reported risk of new-onset seizures after microsurgical resection varies widely, ranging from 3% to 32%. 1,19,29,33,52,66 In contrast, SRS appears to confer a lower seizure risk for patients without pretreatment seizures, with rates ranging from 0% to 7%. 5,33,69 Current treatment options offer relatively effective seizure control with modality-specific risks and complications. However, there remains the issue of whether AVM treatment confers better seizure outcomes than conservative treatment alone. In a recent prospective, populationbased observational study comparing seizure outcomes between AVM treatment and conservative management, Josephson et al. observed no significant difference in the 5-year risk of a recurrent unprovoked seizure between conservative management and AVM treatment (72% vs 67%, respectively; p = 0.6). 36 The same study also found that the 2-year seizure-free rates did not differ significantly between the conservative and treatment groups (57% vs 52%, respectively; p = 0.7). Although the differences were not significant, patients who underwent AVM treatment may have had a higher baseline propensity for seizures, and their seizures may have been refractory to conservative management, thus resulting in AVM treatment. Therefore, the decision to undertake AVM treatment in patients with AVM-associated seizures is complex. Despite the potential benefits for patients with AVM-associated seizures, SRS should typically be recommended to patients for the primary goal of nidus obliteration and hemorrhagic risk reduction. A secondary goal of improving seizure outcomes becomes more compelling when the patient s seizures are refractory to medical management. For patients with persistent seizures in whom complete AVM obliteration was not achieved with SRS, microsurgical resection may be indicated. In fact, SRS treatment generally facilitates subsequent microsurgical resection of AVMs by forming a radiation-induced gliotic capsule around the nidus. 56 Hence, choosing the optimal treatment modality should be tailored to individual patients on a case-by-case basis. Multimodality management may be necessary to optimize seizure control and AVM obliteration in patients with large or complex nidi. Study Limitations This review is limited by the available pooled data from largely retrospective, single-center studies. The method of follow-up evaluation performed at each center may vary, and seizure outcome interpretations may be subjective and biased. In this review we attempted to classify seizure outcomes into broad categories to reduce the nuances separating detailed classification systems. However, the variability in evaluation and interpretation between studies remains difficult to overcome. Baseline characteristics of patients included in this review may vary significantly; not all patients received SRS as the primary or sole treatment. Some patients had prior microsurgical resection and/or embolization of their AVMs. However, data from the studies were insufficient to make such distinctions. The inability of this study to exclude brainstem or cerebellar AVMs may represent a selection bias. Also, results may not be generalizable to all patients because those selected for SRS may have been deemed poor candidates for microsurgery and/or embolization. Although the best efforts were made to select for patients with seizure as the initial presentation, some studies made no distinction between these patients and those with seizure following hemorrhage. These limitations may have influenced the homogeneity of the patient population used in this review. Not all study reports included complete seizure outcome and AVM obliteration rates, leading to 7

8 C. J. Chen et al. exclusion of these studies from certain analyses. In addition, determination of obliteration varied depending on the study center; some studies used MRI, while others performed angiography or a combination of the two. Finally, despite our inclusion and exclusion criteria for this systematic review, certain seizure outcomes remained inconsistently reported. Due to the limitations of the available data, we were unable to distinguish the proportion of patients with drug-resistant epilepsy. For patients who were seizure free, only one study provided the time interval to freedom from AED therapy. 71 In addition, follow-up data for patients who discontinued AEDs were lacking across studies. The data for these patient subpopulations are important to the management and counseling of AVM patients who undergo SRS. Therefore, future AVM radiosurgery studies should strive to obtain detailed seizure outcome data. Conclusions Stereotactic radiosurgery offers favorable outcomes for patients with AVM-associated seizures. Complete AVM obliteration was associated with significantly better seizure outcomes than incomplete obliteration. Future prospective studies are necessary to improve our understanding of the effects of different treatment modalities, patient characteristics, and AVM angioarchitectural features on seizure outcomes in patients harboring AVMs. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Chen, Chivukula, Ding. Acquisition of data: Chen. Analysis and interpretation of data: all authors. Drafting the article: Chen, Chivukula. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. 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10 C. J. Chen et al. 64. Sutcliffe JC, Forster DM, Walton L, Dias PS, Kemeny AA: Untoward clinical effects after stereotactic radiosurgery for intracranial arteriovenous malformations. Br J Neurosurg 6: , Svien HJ, McRae JA: Arteriovenous anomalies of the brain. Fate of patients not having definitive surgery. J Neurosurg 23:23 28, Thorpe ML, Cordato DJ, Morgan MK, Herkes GK: Postoperative seizure outcome in a series of 114 patients with supratentorial arteriovenous malformations. J Clin Neurosci 7: , Turjman F, Massoud TF, Sayre JW, Viñuela F, Guglielmi G, Duckwiler G: Epilepsy associated with cerebral arteriovenous malformations: a multivariate analysis of angioarchitectural characteristics. AJNR Am J Neuroradiol 16: , Waltimo O: The relationship of size, density and localization of intracranial arteriovenous malformations to the type of initial symptom. J Neurol Sci 19:13 19, Wang JY, Yang W, Ye X, Rigamonti D, Coon AL, Tamargo RJ, et al: Impact on seizure control of surgical resection or radiosurgery for cerebral arteriovenous malformations. Neurosurgery 73: , Wolf HK, Roos D, Blümcke I, Pietsch T, Wiestler OD: Perilesional neurochemical changes in focal epilepsies. Acta Neuropathol 91: , Yang SY, Kim DG, Chung HT, Paek SH: Radiosurgery for unruptured cerebral arteriovenous malformations: long-term seizure outcome. Neurology 78: , Yeh HS, Privitera MD: Secondary epileptogenesis in cerebral arteriovenous malformations. Arch Neurol 48: , Zeiler FA, McDonald PJ, Kaufmann A, Fewer D, Butler J, Schroeder G, et al: Gamma knife for cerebral arteriovenous malformations at a single centre. Can J Neurol Sci 38: , 2011 Manuscript submitted February 9, Accepted June 17, Please include this information when citing this paper: DOI: / FOCUS1454. Address correspondence to: Ching-Jen Chen, M.D., Department of Neurological Surgery, University of Virginia Health System, Box , Charlottesville, VA cc5hx@virginia.edu. 10 Neurosurg Focus / Volume 37 / September 2014