Accepted Manuscript Surgical Management of Giant Intracranial Arteriovenous Malformations: A Single Center Experience over 32 years Kevin A. Reinard, MD, Aqueel H. Pabaney, MD, Azam Basheer, MD, Scott B. Phillips, MD, Max K. Kole, MD, Ghaus M. Malik, MD PII: S1878-8750(15)00921-3 DOI: 10.1016/j.wneu.2015.07.051 Reference: WNEU 3079 To appear in: World Neurosurgery Received Date: 21 January 2015 Revised Date: 20 July 2015 Accepted Date: 20 July 2015 Please cite this article as: Reinard KA, Pabaney AH, Basheer A, Phillips SB, Kole MK, Malik GM, Surgical Management of Giant Intracranial Arteriovenous Malformations: A Single Center Experience over 32 years, World Neurosurgery (2015), doi: 10.1016/j.wneu.2015.07.051. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Highlights ●Lack of unified guidelines make treatment of gAVMs a difficult undertaking RI PT ●Surgery will continue to play an important role in the management of gAVMs ●Complications related to treating select gAVMs may be lower than reported in ARUBA AC C EP TE D M AN U SC ●Advanced, multimodal therapeutic approaches can reduce gAVM-related mortality ACCEPTED MANUSCRIPT Pabaney 1 Surgical Management of Giant Intracranial Arteriovenous Malformations: RI PT A Single Center Experience over 32 years Kevin A. Reinard, MD,1 Aqueel H. Pabaney, MD,1 Azam Basheer, MD,1 Scott B. Phillips, MD,2 Max K. Kole, MD,1 Ghaus M. Malik, MD1 Division of Neurological Surgery, Brooks Army Medical Center, San Antonio, Texas, USA M AN U 2 SC From the 1Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, USA; Address correspondence and reprint requests to: TE D Aqueel H. Pabaney, MD Department of Neurosurgery, K-11 Henry Ford Hospital EP 2799 W. Grand Blvd Detroit, Michigan 48202 AC C Phone: 313-916-1094 Fax: 313-916-7139 Email: apabane1@hfhs.org Key Words: Embolization; giant intracranial arteriovenous malformations (gAVMs); hemorrhage; management; microsurgery Running Title: Surgical management of gAVMs ACCEPTED MANUSCRIPT Pabaney 2 Abstract Objective: Treatment of giant intracranial arteriovenous malformations (gAVMs) is a formidable challenge for neurosurgeons and carries significant morbidity and mortality RI PT rates compared to smaller AVMs. In this study, we reviewed the treatments, angiographic results, and clinical outcomes in 64 patients with gAVMs who were treated at Henry Ford Hospital between 1980 and 2012. SC Methods: The AVM database at our institution was queried for patients with gAVMs (≥ 6 cm) and data regarding patient demographics, presentation, AVM angioarchitecture, and M AN U treatments were collected. Functional outcomes as well as complications were analyzed. Results: Of the 64 patients, 33 (51.6%) were female and 31 (48.4%) were male, with an average age of 45.7 years (SD ± 15.5). The most common symptoms on presentation were headaches (50%), seizures (50%), and hemorrhage (41%). The mean AVM size was TE D 6.65 cm (range, 6 to 9 cm). Only 6 AVMs (9.4%) were located in the posterior fossa. The most common Spetzler-Martin (SM) grade was V, seen in 64% of patients. Of the 64 patients 42 (66%) underwent surgical excision, 10 (15.5%) declined any treatment, 8 EP (12.5%) were deemed inoperable and followed conservatively, 2 (3%) had stand-alone embolization, 1 (1.5%) had embolization prior to stereotactic radiosurgery (SRS), and 1 AC C (1.5%) received SRS only. Complete obliteration was achieved in 90% of the surgical patients. Mortality rate was 19% in the surgical cohort as compared to 22% in the observation cohort (p = 0.770). Conclusion: Treatment of gAVMs carries significant morbidity and mortality; however, good outcomes are attainable with a multimodal treatment approach in carefully selected patients. ACCEPTED MANUSCRIPT Pabaney 3 INTRODUCTION Intracranial arteriovenous malformations (AVMs) are one of the most challenging pathologies encountered by cerebrovascular surgeons (1). Management of AVMs is a RI PT daunting task as multiple variables such as patient demographics and presentation, neurological status, angioarchitecture of the AVM (arterial feeders, nidus size, venous drainage, associated aneurysms or varices), availability of multimodality resources, SC expertise of the surgeon or endovascular specialist, and most importantly patient desires must be taken into consideration for any effective treatment algorithm. The optimal M AN U treatment strategy for cerebral AVMs remains controversial (2), especially in light of recent findings from the first randomized trial of unruptured AVMs (ARUBA [A Randomized trial of Unruptured Brain AVMs]) (3). The results of this trial may change the accepted treatment paradigm and challenge the premise that unruptured AVMs should TE D even be treated (4). Microsurgery continues to play a role, albeit controversial, in the treatment of AVMs despite remarkable advances in radiosurgery and endovascular techniques (5–12). EP By definition giant AVMs (gAVMs) measure at least 6 cm in diameter and are categorized, at minimum, as Spetzler-Martin grade III lesions (13). They typically have AC C high-flow, deep venous drainage, and extend into eloquent areas and as a result are associated with higher rates of postoperative complications even in young, healthy patients (14,15). Although endovascular embolization of gAVMs serves as a useful adjunct (16), complete cure is achieved infrequently and may have to be supplemented with surgical excision or radiosurgery (9,17–19). ACCEPTED MANUSCRIPT Pabaney 4 In this paper, we report the senior author’s (G.M.M.) experience with 64 patients harboring gAVMs and outcomes over a span of 32 years. RI PT METHODS In accordance with the Henry Ford Hospital Institutional Review Board (IRB #8179), we searched our AVM database from 1980 to 2012 and identified 64 patients with gAVMs SC who were evaluated and treated at our institution. In all patients, gAVMs were diagnosed as nidus size greater than 6 cm on the basis of available magnetic resonance imaging M AN U (MRI) studies as well as mid-arterial phase digital subtraction angiography (DSA). Electronic medical records were searched to gather patient demographic data including age, gender, symptoms on presentation, and presence or absence of intracerebral hemorrhage (ICH) on computed tomography (CT) scan. We also collected information TE D about the location of the AVM nidus, arterial feeders and venous drainage, as well as the presence of flow-related aneurysms (feeding artery, intranidal, or venous). Spetzler – Martin (SM) grading scale (20) was applied to all patients to assess surgical risk. Patients EP underwent 6-vessel cerebral angiography post-treatment, and the results were examined to assess obliteration status at the end of treatment. Medical records were screened to AC C assess patients’ functional status prior to treatment, immediately post treatment, and later in the follow-up period. A modified Rankin score (mRS) was assigned for each interval, and the duration of follow-up was noted. For statistical analyses, Chi-square tests were performed to assess the association between clinical variables and treatment options rendered and functional outcomes. ACCEPTED MANUSCRIPT Pabaney 5 Furthermore, we performed a survival analysis. All testing was done at 0.05 level using SAS version 9.4. RESULTS RI PT Our institutional review revealed 64 patients evaluated for gAVMs between 1980 and 2012 (Table 1), with an average age of 45.7 years (± 15.5). There were 33 (51.6%) female and 31 (48.4%) male patients. The most common presenting symptoms were SC headaches (32/64, 50%), seizures (32/64, 50%), followed by hemorrhage (26/64, 41%), diplopia (2/64, 3%), ataxia (1/64, 1.6%), tinnitus (1/64, 1.6%), and altered mental status M AN U (1/64, 1.6%). In our series, the AVM was located in the left cerebral hemisphere in 26 patients (40.6%), in the right cerebral hemisphere in 32 (50%) patients, and in the cerebellar hemispheres in 6 (9.4%) patients. Of the 58 AVMs (91%) located in the supratentorial compartment, 19 (33%) were fronto-parietal, 11 (19%) were parieto- TE D occipital, 7 (12%) were parieto-temporal, 5 were purely frontal, 4 were fronto-temporal, 3 were purely temporal, 2 were purely parietal, 2 were located in the Sylvian fissure, 2 were in the corpus callosum, 1 was located in the occipital lobe, 1 was temporal-occipital, EP and 1 was confined to the basal ganglia (Table 2). Only 3 (4.7%) patients had a single arterial territory feeder. Eighteen (28%) patients had flow-related aneurysms while 8 AC C (12.5%) had venous aneurysms. The average size of the AVM nidus was 6.65 cm (range 6.0 – 9.0 cm). Of the 64 gAVMs, only 1 (1.6%) was classified as SM grade III, 22 (34.4%) as SM grade IV, and the majority as SM grade V (41, 64%). Of the 6 (9.4%) cerebellar lesions, half were located in the cerebellar hemispheres and half were located in the vermis; the majority of the posterior fossa gAVMs (67%) included the deep cerebellar nuclei. ACCEPTED MANUSCRIPT Pabaney 6 Twenty-six (41%) patients underwent surgical resection without prior embolization, whereas 16 (25%) underwent microsurgical extirpation after partial embolization of their gAVM. Overall, 42 (66%) patients underwent microsurgical RI PT excision. Two (3%) patients were treated with embolization only. Stereotactic radiosurgery (SRS) was performed on two patients (3%), one of which underwent preSRS embolization. Ten patients (15.6%) declined any treatment and we elected to SC observe the eight patients (12.5%) with inoperable lesions (i.e. basal ganglia involvement, large bilateral lesions involving the corpus callosum, and arterial supply M AN U from deep perforators). Except for the seven patients (11%) who died while hospitalized, all patients underwent postoperative cerebral angiogram to assess AVM obliteration status. Follow-up angiograms were not performed in patients who did not receive treatment either because they harbored inoperable lesions or because they opted for TE D medical management (18 patients total, 28%). Of the 39 patients who had a postoperative angiogram, 35 had complete obliteration of their gAVM (90%) and only 4 (10%) had partial obliteration with residual AV shunting. Of the 4 patients with incomplete EP obliteration, 2 had received SRS, 1 received stand-alone embolization, and 1 underwent microsurgical resection. Only 1 patient out of the 42 who had surgical resection (2.4%) AC C had residual AV shunting on postoperative angiogram. Patients were followed-up for a mean of 73.73 months (± 98.25). On presentation, the mRS of the entire cohort was as follows: 1 (1.5%) patient had mRS of 0, 27 (42%) had mRS of 1, 19 (30%) had mRS of 2, 17 (26.5%) had mRS of 3, and no patients had mRS of 4-5. At the earliest follow-up (< 3 months after initial encounter), the mRS of all patients, irrespective of whether they received treatment or not, changed to the following: ACCEPTED MANUSCRIPT Pabaney 7 no patients had mRS of 0, 5 (8%) had mRS of 1, 15 (23%) had mRS of 2, 19 (30%) had mRS of 3, 13 (20%) had mRS of 4, 3 (5%) had mRS of 5, and 9 (14%) had mRS of 6 (died). At long-term follow-up (> 3 months after initial encounter), 4 additional patients RI PT had died and the mRS of the remaining cohort was as follows: 3 (5%) patients had mRS of 0, 5 (8%) had mRS of 1, 11 (17%) had mRS of 2, 17 (26%) had mRS of 3, 3 (5%) had mRS of 4, and 2 (3%) had mRS of 5. Ten patients (15%) were lost to follow-up (Figure SC 1). Four (22%) of the patients who did not receive any treatment died as compared to 9 (19.6%) who underwent either microsurgical resection (8 patients) or stand-alone M AN U embolization (1 patient). Overall mortality rate was 20% (Table 3). To assess whether the advent of new endovascular micro-catheters or liquid embolic agents had an impact on our patient outcomes, we divided our series into early (1980 – 2000) and late (2000 – 2012) surgical groups. Thirty (71.4%) patients underwent TE D surgery prior to 2000, while 12 (28.6%) had microsurgical resection after 2000. Within the early cohort, 25 (83.3%) patients had surgery without embolization and 5 (16.7%) had preoperative embolization. In contrast, 11 (92%) patients in the late cohort had EP preoperative embolization with only 1 (8%) undergoing surgery without prior embolization. Overall, only 4 (13.3%) patients had good outcomes (mRS ≤ 2) (21) in the AC C early group at long-term (> 3 months) follow-up. Good outcomes improved to 58.3% in the late group at long-term follow-up (p < 0.001). Comparison of the early and late surgical groups also revealed that poor outcomes (mRS > 3) (22) declined significantly in our series from 86.7% before 2000 to 41.7% after 2000 (p < 0.001) (Figure 2). To better elucidate whether the surgical group exhibited a different survival pattern at different time intervals as compared to the observation group, we also ACCEPTED MANUSCRIPT Pabaney 8 performed a survival analysis using Kaplan-Meier methods. For the surgical group, four patients died within 30 days of treatment and 1 died between 1 and 2 months post treatment. The 1, 5, and 10 year overall survival rates for patients with surgery were RI PT 89%, 72%, and 63% respectively while for patients without surgery the rates were 88%, 80%, and 66%. The difference in overall survival rates was not significant (p = 0.330, SC log-rank test) (Figure 3). ILLUSTRATIVE CASES M AN U Case 5: A 20-year-old, right-handed male presented to our emergency department with acute onset headaches, speech difficulty, and weakness. On examination, he was awake, dysphasic, and had right hemiparesis with strength of 2/5 on the Medical Research Council (MRC) scale (23). Initial head CT revealed intraventricular hemorrhage (IVH) TE D and minimal subarachnoid hemorrhage (SAH) (Figure 4A). An external ventricular drain (EVD) was placed. Cerebral angiography revealed a 7.4 cm, left parietal gAVM involving the motor and premotor areas (Figure 4B). The arterial supply to the gAVM EP was from branches of the left middle cerebral artery (MCA) and the anterior cerebral artery (ACA). The venous drainage was superficial to both the transverse and superior AC C sagittal sinuses as well as deep into the vein of Galen (SM grade V). Preoperative embolization was performed over three different sessions using N-butylcyanoacrylate (NBCA), which led to a moderate reduction in the AVM's size (Figure 4C). The patient was taken to the operating room several days after the last embolization session for microsurgical extirpation of the gAVM (Figure 4D). Postoperative angiography revealed complete AVM resection with no evidence of arteriovenous shunting (Figure 4E). In the ACCEPTED MANUSCRIPT Pabaney 9 recovery phase, the patient had slight improvement of his right hemiparesis and near complete resolution of his dysphasia. He developed postoperative seizures that were well controlled with one medication. At his last office visit seven years after surgery, he had RI PT completed a college degree and was able to drive independently. Case 20: A 23-year-old, right-handed male presented to our emergency department after he was found unconscious following an episode of visual flashes suggestive of a seizure. SC Neurological examination was unremarkable. Initial imaging studies revealed a right temporal-occipital gAVM with no evidence of hemorrhage (Figure 5A). Cerebral M AN U angiography confirmed a 7-cm right temporal gAVM. Arterial feeders arose from the MCA and the posterior cerebral artery (PCA). The venous drainage was superficial through veins of Labbé and Trolard and deep through the basal vein of Rosenthal (SM IV) (Figure 5B and 5C). The patient underwent staged preoperative embolization and TE D arterial feeders from the MCA and the PCA were successfully occluded using Onyx-18 and Onyx-34. Postembolization angiogram continued to show vigorous filling of the AVM (Figure 5D). He was then taken to the operating room for surgical removal of the EP gAVM. Microsurgical dissection was initiated at the superior margin of the AVM just below the Sylvian fissure and continued circumferentially around the gliotic margin until AC C the entire AVM was excised. Postoperative angiogram revealed complete resection of the AVM (Figure 5E). Following his treatment, the patient developed a left superior quadrantonopsia; however, he became seizure-free. At the last follow-up visit, three years following surgery, his visual field defect had persisted but did not influence his daily functioning. ACCEPTED MANUSCRIPT Pabaney 10 Case 37: A 42-year-old male was referred to our department in the mid-1980s after imaging performed for persistent headaches and a new onset left hemiparesis revealed a ruptured AVM (Figure 6A). Neurological examination revealed right-sided hemiparesis, RI PT 3/5 on MRC scale. Cerebral angiogram demonstrated an 8-cm, right frontal-parietaloccipital gAVM with arterial feeders from the ACA, MCA, and PCA as well as perforating branches of the right anterior choroidal (ACh) and lenticulostriate arteries SC (LSt). Contralateral ACA and LSt also supplied blood to the AVM. Venous drainage was both superficial and deep with an associated large venous aneurysm (SM V) (Figure 6B- M AN U E). Without preoperative embolization, the patient underwent microsurgical resection. Intraoperatively, severe bleeding was encountered from the deep perforating vessels that retracted into the white matter. Commando resection of AVM was performed (24). The patient suffered from recurrent ICH in the postoperative unit, possibly secondary to TE D consumptive coagulopathy, and died a few days later. Case 13: A 28-year-old right-handed male presented initially to his primary care physician with complaints of right temporal headaches and progressive left-sided EP weakness for 2 years. On examination he was found to have mild left hemiparesis, 4/5 on the MRC scale. MRI of the brain revealed minimal SAH and a gAVM with diffuse nidus AC C (approximately 6 cm) in the right basal nuclei, internal capsule, and insular cortex with mass effect on the ipsilateral ventricle (Figure 7A and 7B). Cerebral angiography revealed an arterial supply primarily from the LSt, the ACA, and the MCA (SM V) (Figure 7C). Given the eloquent location and the diffuse angioarchitecture of the AVM, no treatment was offered. At his last follow-up visit 3 months after the initial diagnosis, the patient continued to have headaches with stable left hemiparesis. ACCEPTED MANUSCRIPT Pabaney 11 DISCUSSION The incidence of AVMs is 1-1.4 cases per 100,000 persons with an overall annual rate of RI PT hemorrhage that is approximately 2% to 4% in untreated patients (25). Recent, largescale, pooled analyses have corroborated these findings and estimated the annual hemorrhage rate to be 3% (26). Female sex, advanced age, subcortical location, prior SC rupture history, deep venous drainage, and association with intracranial aneurysms are independent risk factors that could increase the risk of hemorrhage (26–28). While M AN U headache, focal neurologic deficits, and seizure activity are common presenting symptoms, nearly 50% of all AVMs result in hemorrhages that cause permanent neurologic morbidity and mortality in 30% of the adult population (11). AVMs with nidus measuring 6 cm or more in maximum diameter are considered TE D giant AVMs (13). By virtue of size alone these are classified according to the SpetzlerMartin (SM) grading scale as grade III or higher and because most harbor deep venous drainage and are proximal to eloquent structures, they may be considered formidable and EP “inoperable” lesions by even experienced neurosurgeons (29). Only a few reports have focused on the natural history of gAVMs exclusively AC C because these lesions are most commonly presented as a small subset in larger case series (25,26,30,31). Therefore, the natural history of gAVMs remains unclear and is further confounded by conflicting evidence regarding AVM size and relative risk of hemorrhage. Fults and Kelly found no correlation between AVM size and risk of hemorrhage (32). Crawford et al followed 217 unruptured AVMs and reached the same conclusion (33). Zhao and colleagues found an annual hemorrhage rate of 1.4% in 40 patients with ACCEPTED MANUSCRIPT Pabaney 12 gAVMs (34). In a retrospective cohort of 73 patients with SM grade IV and V AVMs, Han et al noted a 1.5% hemorrhage rate (35). Stefani and colleagues in Toronto prospectively followed 390 patients with large AVMs for an average of 3.1 years and RI PT concluded that large AVMs bleed more frequently than small lesions (Odds Ratio, OR 2.5) (36). Hernesniemi et al. reported an annual hemorrhage rate of 3.5% for AVMs larger than 5 cm (37) and Laakso et al reported an annual hemorrhage rate of 3.3% in a SC cohort of 63 patients who harbored SM IV and V AVMs (38). Other studies have suggested that the rate of hemorrhage in unruptured gAVMs is approximately 10% to M AN U 20% in the first five years and the rate of rupture could increase dramatically to 50% after 20 years (33,34,37,39). Because of the foregoing, and in conjunction with the absence of evidence-based guidelines, the management of gAVMs remains a controversial and formidable challenge TE D that is best undertaken with caution and at neurovascular centers with multimodal capabilities dedicated specifically to the treatment of gAVMs. At our institution, every patient harboring a giant vascular malformation is presented to a panel of cerebrovascular EP surgeons, endovascular specialists, neuro-interventionalists, and stroke neurologists at a weekly vascular conference. It has generally been our practice to consider patients with AC C significant hemorrhage, progressive neurological deficits, intractable seizures or headaches, hemodynamic steal phenomenon, large pre- or intra-nidal aneurysms, or venous outflow restrictions for intervention. After taking into consideration each patient’s desire and only if the vascular board has rendered a consensus opinion for treatment do we go ahead with intervention. Since pre-operative embolization has ACCEPTED MANUSCRIPT Pabaney 13 significantly improved our outcomes, all patients considered for microsurgical resection undergo pre-operative embolization. Microsurgical resection, in select cases, can offer durable and high cure rates with RI PT immediate elimination of future hemorrhage risk (5,34,40). Preoperative endovascular embolization using particle or liquid embolic materials may potentially make surgical excision of these AVMs less daunting by reducing operative time and decreasing blood SC loss (10,41). However, endovascular interventions can rarely treat gAVMs completely and must be followed by surgical extirpation or radiosurgery (9,34). The goal of M AN U managing AVMs should always be complete obliteration regardless of the AVM grade, because partially treated AVMs present a substantially higher risk of hemorrhage (35,42,43). Several authors have reported their experience with the surgical management of TE D gAVMs. Spetzler and Martin reported a series of 20 patients with gAVMs managed with staged embolization and surgical resection. Complete excision was accomplished in 18 of these patients (44). Han et al., however, in a series of 73 patients with SM IV and V EP AVMs had an overall hemorrhage rate of 1.5% per year. Their final recommendation was that high-grade AVMs should be followed expectantly (35). In a series of 90 patients AC C Hernesniemi et al. reported on 15 patients with AVMs greater than 5 cm in diameter (44). Of these patients, 5 had excellent outcomes, 6 had moderate disabilities, 1 had a severe disability, 1 died, and 2 were lost to follow-up (45). Chang and Steinberg presented their cohort of 53 patients harboring gAVMs that were treated with surgery, embolization and radiosurgery. About 70% of their patients were cured but morbidity and mortality rates reached 30% (31). Recently, Zhao and colleagues reported surgical outcomes for 40 ACCEPTED MANUSCRIPT Pabaney 14 patients with gAVMs. Half of the patients developed complications in the immediate postoperative period, 23.3% had a neurological deficit at last follow-up, and 10% of the patients died (34). RI PT Endovascular techniques have proved valuable adjuncts in the management of cerebral AVMs. Successful embolization can partially occlude the AVM and make possible the surgical resection of an otherwise inoperable lesion (10,41). Associated SC aneurysms an also be occluded by endovascular means prior to addressing the AVM surgically (46). Additionally, radiosurgery following AVM embolization has been M AN U successfully undertaken for the treatment of large AVMs with reasonable success (19). However, despite significant advances, endovascular interventions can rarely achieve complete AVM obliteration and may need to be supplemented with surgery or radiation. According to a recent meta-analysis, morbidity and mortality related to endovascular (47). TE D procedures for definitive AVM treatment occurred in 6.6% of patients (range, 0%–28%) Radiation therapy, in the form of radiosurgery and hypofractionated radiotherapy, EP has also played a significant role in the treatment of AVMs. Single-fraction SRS has proven effective in treating AVMs with nidal volumes less than 14 cm3 or 3 cm in AC C diameter, with complete occlusion rates reported at 72% to 96% (48–51); however, larger lesions have resulted in lukewarm results (52–54). Several studies have demonstrated that both non-obliteration and complication rates rise when AVMs exceed 10 cm3. Pan et al. followed 240 patients with AVMs treated by gamma knife radiosurgery and found that only 25% of patients with large AVMs (≥ 15 cm3) were cured with singledose SRS. When treatment of large lesions was compared to that of smaller lesions, ACCEPTED MANUSCRIPT Pabaney 15 patients with larger lesions suffered more adverse radiological effects including permanent neurological deficits (55). Hypofractionated stereotactic radiotherapy (HSRT), 4-7 Gy/fraction for 4-6 weeks for a total of 28-42 Gy, has also been utilized for treatment RI PT of inoperable gAVMs that cannot be effectively and safely treated with single-fraction SRS. Comparison of radiographic outcomes between SRS and HSRT has shown no inferiority of AVM obliteration rate with HSRT (56). More recently, Lawton and SC colleagues reported their experience with 16 patients harboring high-grade AVMs that were treated with volume-staged radiosurgery for downsizing the AVM followed by M AN U microsurgical excision. They were able to cure 93.8% of patients with 19% morbidity and mortality (57). Endovascular embolization followed by SRS has also been used for medium and large size AVMs (19). The premise behind the use of pre-radiosurgical embolization is to reduce the effective size of AVM nidus and make it more manageable TE D for radiosurgery. Unfortunately, several studies have shown that overall outcomes as well as obliteration rates are worse in patients undergoing embolization prior to radiosurgery (58). Plausible explanations for this paradox are the possibility that radio-opaque EP materials may scatter radiation and result in decreased radiation absorption by the nidal vessels, and that the altered flow dynamics may not only increase the difficulty of AC C planning for radiosurgery but also the rates of hemorrhage following embolization. Interestingly, however, Veznedaroglu et al. reported increased rates of obliteration in patients with large AVMs undergoing embolization prior to fractionated stereotactic radiotherapy (59). Because of the senior author’s (G.M.M.) experience with microsurgical resection of AVMs, our institution has not been a major referral center for radiosurgical treatment of AVMs, and this is evidenced by the two patients who ACCEPTED MANUSCRIPT Pabaney 16 underwent SRS in our series. As a result, we cannot effectively make conclusions about the impact of radiation therapy on our patients with gAVMs. Although the cohort presented in this report comprises 64 patients only, careful RI PT analysis of our findings could provide important lessons. First, the gAVMs in our series most commonly involved the frontal, parietal, and occipital lobes, which has important implications (Table 2). Regardless of the laterality of the AVM, resection of gAVMs SC from the parietal lobe will invariably lead to motor, visual, or neuropsychological deficits unlike lesions located purely in the frontal lobe, and this fact should be discussed at M AN U length with the patient prior to beginning any treatment. As seen in Figure 1, the functional independence of several patients declined after treatment, reflecting the high risk associated with any treatment of AVMs, especially with high-grade lesions, a fact that is corroborated by other reports (60) and may push the clinician to consider TE D alternatives to microsurgery such as SRS (61). Second, complete obliteration rates did not differ significantly between supratentorial AVMs of various SM grading. In contrast, the lowest complete obliteration rates in our series were observed in lesions located in the EP cerebellum (Table 4). Nearly 70% of patients harboring posterior fossa gAVMs presented with ICH. Three of the patients with posterior fossa gAVMs (50%) died after AC C intervention as compared to the only 6 patients (10%) with supratentorial gAVMs who died after any intervention. It is also important to note that five patients (83.3%) with infratentorial gAVMs had poor outcomes (mRS ≥ 3) underscoring that the posterior fossa AVMs may have a more ominous natural history (62) as compared to their supratentorial counterparts and, perhaps, should be considered as an entirely separate entity. Third, the rates of complete obliteration were highest when a combination of preoperative ACCEPTED MANUSCRIPT Pabaney 17 embolization and microsurgical excision was utilized to treat AVMs (Table 5). Complete obliteration was achieved in 94% of cases when embolization preceded surgery. This rate dropped to 77% when preoperative embolization was not utilized prior to surgery. More RI PT importantly, none of the patients who underwent stand-alone embolization or SRS exclusively (or any combination of these two modalities) achieved complete AVM obliteration. Therefore, microsurgery should be considered a viable option if multimodal SC treatment is entertained and complete cure is the objective. Fourth, of the 46 patients who received any mode of therapy (42 microsurgery, 1 SRS, 1 embolization + SRS, and 2 M AN U embolization only), 7 (16.7%) died due to complications related to ICH. Mortality rate was 19% for patients who underwent microsurgical resection with or without adjunctive embolization. In contrast, of the 18 patients who did not receive any treatment (8 deemed inoperable, 10 declined any treatment), 4 (22.2%) died as a result of ICH. Our overall TE D mortality rate of 20% is higher than what has been reported in the past by Zhao et al (10.2%) and Chang et al (15%) (31,34). Although the difference in mortality between the treatment and observation groups is not significant (19.6% vs. 22.2%, p = 0.810), our EP observed rate of stroke or death among treated patients was lower than reported in ARUBA and other recent reports questioning intervention for AVMs (3,4). Fifth, while AC C endovascular technique have been invaluable adjuncts in the diagnosis and treatment of AVMs since the 1960s (41), advances in catheter angiography as well as liquid embolic agents (Onyx) in the late 1990s and early 2000s revolutionized the treatment of AVMs and ushered in a new era of treatment (41,63). As our experience with microsurgical treatment of AVMs increased, the addition of new micro-catheters and liquid embolic agents augmented our outcomes while simultaneously lowering our overall morbidity and ACCEPTED MANUSCRIPT Pabaney 18 mortality. This is evidenced by a reduction in our poor outcomes (mRS ≥ 3) from 86.7% before 2000 to 41.7% after 2000 (p < 0.002). Nowadays, all patients considered for surgical obliteration of AVMs routinely undergo catheter angiography with intent to RI PT eliminate arterial pedicles and possibly reduce AVM nidus prior to definitive operative intervention. And sixth, our survival analysis confirms that microsurgical resection of gAVMs in carefully selected patients does not reduce survival rate by transferring SC additional harm to patients. Our analysis demonstrates that not all giant AVMs are created equal and, therefore, should not automatically be dismissed as “inoperable” M AN U lesions. Rather, healthy young patients with high lifetime risks of rupture should be considered for microsurgical resection of their gAVM with pre-operative embolization because it may offer them a legitimate chance of cure. It is important to acknowledge several key limitations of our study. We realize TE D that retrospective analyses are fraught with inherent biases such as sampling bias. Because many patients in our analysis received their care prior to 1994 when electronic medical records were implemented at Henry Ford Hospital, information used to calculate EP mRS for many patients was limited and we had no choice but to rely on telephone conversations with patients or family members to assess functional outcomes. While AC C recent reports have shown mRS scores applied by telephone to be reliable (64), others have questioned the interobserver reliability of mRS in stroke patients altogether (65). We also understand that results from a subset of patients should not be generalized to a larger population. Rigorous meta-analyses are required to reach evidentiary conclusions regarding treatment of high-grade AVMs because randomized controlled trials may not ACCEPTED MANUSCRIPT Pabaney 19 be ethically feasible. We hope that our results will further our understanding of these complex lesions and help guide the future management of gAVMs. RI PT CONCLUSION An ongoing challenge for cerebrovascular surgeons will be the development of a management algorithm for patients with giant AVMs that will ensure durable and SC complete obliteration rates while minimizing patient morbidity. Advances in radiation and endovascular therapy bring hope that new treatment paradigms will emerge, enabling M AN U physicians to treat these complicated lesions with uniformity. Until then, decisions on whether to treat giant AVMs should be made on an individual basis and at dedicated cerebrovascular centers with multidisciplinary resources at their disposal including AC C EP TE D microsurgery. ACCEPTED MANUSCRIPT Pabaney 20 REFERENCES 1. Peschillo S, Caporlingua A, Colonnese C, Guidetti G: Brain AVMs: An 2. RI PT endovascular, surgical, and radiosurgical udate. Sci World J 2014:834931, 2014. 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Savio K, Pietra GLD, Oddone E, Reggiani M, Leone MA: Reliability of the modified Rankin Scale applied by telephone. Neurol Int 5(1):e2, 2013. EP 65. Quinn TJ, Dawson J, Walters MR, Lees KR: Reliability of the modified Rankin AC C Scale: a systematic review. Stroke J Cereb Circ 40(10):3393–3395, 2009. ACCEPTED MANUSCRIPT Pabaney 29 Figure Captions: Figure 1: Bar graph illustrating distribution of patient cohort across mRS scores 0 – 6 at the time of presentation, at early (< 3 months), and late (> 3 months) follow-up periods. RI PT Figure 2: Flow diagram depicting relative outcomes in patients treated with microsurgery prior to and after the year 2000. Figure 3: Kaplan-Maier survival analysis demonstrating that there was no statistically SC significance difference in the rates of 1, 5, and 10-year survival between the microsurgical and observation groups. M AN U Figure 4. A: Axial CT head obtained at initial presentation showing intraventricular hemorrhage (IVH) in the left lateral ventricle. B: Anteroposterior projection of the left ICA injection showing a giant AVM fed by branches of the MCA and ACA and early venous drainage into the superior sagittal sinus and vein of Galen. C: Anteroposterior projection of the left ICA injection obtained postembolization, showing persistent filling of the AVM. D: Intraoperative picture of the AVM surgical extirpation. TE D obtained after opening the dura. E: Angiogram revealing complete obliteration of the AVM by Figure 5. A: Axial T2 – weighted MRI obtained at initial presentation shows multiple flow voids EP and a large nidus suggestive of a giant AVM located in the right temporal lobe. B: Lateral projection of a vertebral artery injection shows a giant AVM fed by branches of the PCA and AC C early venous drainage into the deep system. C: Anteroposterior projection of the right ICA injection shows filling of the AVM by the branches of the MCA. D: Cerebral angiogram obtained post-embolization shows residual filling of the AVM despite three embolization attempts with Onyx. E: Angiogram revealing complete surgical resection of the AVM. Figure 6. A: Axial CT head obtained at initial presentation showing evidence of subarachnoid hemorrhage and a large tangle of vessels in the midline. B: Lateral projection of right ICA injection shows a giant AVM fed by branches of the MCA and a large venous aneurysm. C and E: Lateral and AP projection of the left vertebral artery injection shows filling of the posterior ACCEPTED MANUSCRIPT Pabaney 30 compartment of the AVM by the PCA. D: Lateral projection of left ICA injection shows filling of AVM fed by ACA. Figure 7. A and B: Coronal and axial T2-weighted M images obtained at time of initial RI PT presentation show a giant AVM nidus and multiple flow voids in the right basal ganglia, internal capsule and insula. Appreciate the effacement of the right lateral ventricle caused by the mass effect. C: Lateral projection of the right ICA injection shows that AVM is fed primarily by the AC C EP TE D M AN U to treat it safely by surgical or endovascular means. SC perforating vessels (lenticulostriate branches) of the ICA, MCA and ACA, making it a challenge ACCEPTED MANUSCRIPT Table 1 Patient demographics and AVM characteristics. Age Sex Present. Location (cm) S Arterial M Feeders Treat. Initial F/u mRS F/u AVM mRS Early Late (mo) Obliteration 2 177 Complete Field cut* 3 6 36 - Death 2/2ICH 1 1 62 Complete Chronic HA 64 M HA, ICH 6 R, P-O 4 A/M/PCA Sx 1 2 56 F ICH, Sz 7 R, F-P 4 ACh, MCA, NR 3 E + Sx ThP 50 M Diplopia 6 R, P-O 4 M/PCA 4 48 F HA, ICH 7 Vermis 5 A/PICA, SCA Sx 3 5 6 0 Complete PVS and WD 5 20 M ICH 7 L, F-P 5 A/MCA E + Sx 3 3 3 82 Complete Aphasia, paresis* 6 54 F HA, ICH 6 R Sylvian 4 MCA Sx 1 4 Lost 2 Complete Field cut, plegia* 7 35 M Sz 6 L, T-P 5 ACh, MCA Dec. 2 2 2 89 - Chronic Sz 8 49 F HA, ICH 6 L, P-O 5 A/M/PCA Dec. 3 3 6 480 - Death 2/2 ICH 9 41 M Sz 6 L, T 5 ACh,M/PCA Sx 2 5 Lost 3 Complete Aphasia, plegia 10 50 M Sz 7 R, PO, 5 M/PCA NR 2 2 2 268 - Chronic Sz AC C EP TE D M AN U 3 CC 1 Complication 3 1 SC (yrs) Size RI PT Pt. 11 13 M Sz 7 L, P, CC 5 A/M/PCA E + Sx 3 3 3 78 Complete Paresis 12 64 M Sz 6 R, F 5 A/MCA Dec. 1 1 0 126 - None 13 28 M ICH, Sz 6 R, BG 5 A/M/PCA NR 3 3 3 3 - Paresis 14 41 F HA 6 L/R, P-O 5 A/M/PCA NR 1 3 5 312 - PVS 49 M HA, ICH 7 Vermis 4 SCA Sx 1 3 3 25 Complete Truncal ataxia 16 50 M HA, ICH 8 R, P 4 A/M/P E + Sx 1 4 3 171 Complete Paresis 17 17 F HA, Tin. 9 Cerebell. 5 SCA, PCA E + Sx 1 6 - 0 Complete Death 2/2 ICH 18 35 M HA 6 R, P-O 4 M/PCA Sx 1 4 3 65 Complete Field cut, paresis 19 65 F Sz 6 R, F-P 4 A/MCA Sx 2 20 23 M ICH, Sz 7 R, T-O 5 M/PCA E + Sx 2 21 22 F Sz 6 L, O 5 A/MCA SRS 22 53 F HA, ICH 6 R, T-P 5 A/M/PCA Sx 23 34 M HA, ICH 6 L, P-T 5 M/PCA E+ RI PT 15 SC ACCEPTED MANUSCRIPT 3 3 32 Complete Paresis 2 1 40 Complete Field cut 2 Lost 3 Partial Field cut, Sz 1 4 3 12 Complete Field cut, paresis 2 2 2 98 Partial Sz 3 2 2 96 - HA, paresis M AN U 1 33 M HA 6 L, F-P 5 A/MCA, LStr Dec. 25 59 F HA, Sz 8 R T-P-O 5 A/M/PCA E + Sx 2 4 3 30 Complete Paresis 26 30 F HA 9 R, F-T 4 A/M/PCA Sx 1 6 - 0 - Death 2/2 ICH 27 38 F Ataxia 6 Cerebell. 5 A/PICA, SCA Sx 2 5 5 7 Partial PVS 2/2 ICH 28 58 M SZ 7 L Sylvian 5 M/PCA Dec. 2 2 2 184 - Sz 29 20 M HA, ICH 6 L, F-P 5 A/M/PCA Sx 1 3 2 16 Complete Sz 30 27 F AMS 7 Vermis 4 A/PICA, SCA NR 1 1 Lost 13 - Hydrocephalus 31 64 M ICH, Sz 6 L, T-P 4 A/M/PCA Sx 2 6 - 0 - Death 2/2 ICH 32 44 F SZ 6 L, T-P 4 A/MCA, PChA E + Sx 1 3 1 181 Complete HA 33 61 F HA, ICH 8 L, T 5 M/PCA, AChA E + Sx 1 2 1 231 Complete Hydrocephalus AC C TE D 24 EP SRS 85 F ICH, Sz 6 R, P-O 4 A/PCA E + Sx 3 2 2 35 26 M HA, ICH 8 R, F-P 5 A/M/PCA Sx 3 4 Lost 36 58 F ICH, Sz 7 R, F 4 A/MCA E + Sx 2 4 3 37 42 M HA, ICH 8 R, F-T-P 5 A/M/PCA Sx 3 6 - 38 54 F Sz 8 L, F-P 4 A/M/PCA NR 2 39 39 F Sz, ICH 6 R, F-P 5 A/M/PCA E + Sx 3 40 62 F Diplopia 6 R, P-O 5 A/M/PCA Dec. 41 43 F SZ 6 R, P 4 A/M/PCA E + Sx SC 42 58 F HA, ICH 7 L, F-P 5 ECA, M/PCA 43 50 F HA, ICH 8 L, F-P 5 A/M/PCA 44 55 F SZ 6 R, F-P 5 A/MCA 45 65 F HA, ICH 6 Cerebell. 5 A/PICA, SCA 46 32 M ICH 8 R, T 5 ECA, A/PCA 47 75 F HA, Sz 6 L, P-O 4 48 70 F Sz 8 L, F-P 5 49 44 F HA, ICH 6 L, P-O 50 48 M HA 6 51 47 F HA 52 37 M 53 46 F RI PT 34 EP ACCEPTED MANUSCRIPT 19 Complete Filed cut, Dpress Complete Plegia 11 Complete Paresis 0 - Death 2/2 ICH 3 3 253 - Paresis, Sz 3 2 27 Complete Sz 2 4 240 - Field cut, plegia 1 2 0 75 Complete None E only 3 6 - 0 - Death 2/2 ICH E + Sx 3 6 - 0 - Death 2/2 ICH Dec. 1 6 - 1 - Death 2/2 ICH Sx 1 6 - 1 - Death 2/2 ICH NR 3 4 4 46 - Plegia M/PCA Dec. 1 1 Lost 3 - Sz A/M/PCA Dec. 1 2 6 120 - Death 2/2 ICH 5 A/M/PCA E + Sx 3 4 3 117 Complete Paresis R, F 4 ECA, M/PCA Sx 3 6 - 0 - Death 2/2 ICH 6 L, F-T 5 A/MCA Sx 2 4 3 123 Complete Aphasia HA, Sz 6 R, F-P 5 A/MCA E + Sx 2 3 Lost 2 Complete Paresis, Sz HA, ICH 7 L, P-O 4 A/M/PCA Sx 3 3 Lost 2 Complete Field cut AC C TE D M AN U 2 38 M HA, Sz 6 L, F-T 4 MCA, PCA Dec. 1 2 2 47 - Sz 55 45 M HA, Sz 7 L, P-O 5 A/M/PCA Sx 2 3 3 36 Complete Paresis 56 28 M Sz 6 R, F 3 A/MCA Sx 1 1 0 36 Complete None 57 47 F HA 6.5 L, F-P 5 A/M/PCA Sx 0 4 Lost 3 Complete Aphasia, paresis 58 46 F Sz 7.5 R, T-P 5 A/M/PCA Sx 1 59 37 M Sz 7.0 R, F-P 5 A/M/PCA Sx 2 60 32 F HA, Sz 6 R, F-P 5 A/MCA Sx 61 58 M HA, Sz 6 L, F 4 A/MCA E only 62 34 M Sz 6 R, F-P 4 A/MCA 63 66 M Sz 6.5 R, F-P 5 A/MCA 64 55 M Sz 7 R, F-P 5 A/MCA RI PT 54 SC ACCEPTED MANUSCRIPT 3 Lost 2 Complete Paresis 4 3 252 Complete Paresis 4 4 18 Complete Plegia 1 2 1 213 Partial HA Sx 2 3 3 8 Complete Paresis Sx 1 3 3 10 Complete Paresis NR 1 2 2 58 - HA TE D M AN U 2 HA, headache; Sz, seizure; ICH, intracerebral hemorrhage; AMS, altered mental status; Tin, tinnitus; R, right; L, left; F, frontal; T, temporal; P, parietal; EP O, occipital; Cerebell., cerebellar; CC, corpus calloum; ACA, anterior cerebral artery; ECA, external carotid artery; MCA, middle cerebral artery; PCA, AC C posterior cerebral artery, AICA, anterior-inferior cerebellar artery, PICA, posterior-inferior cerebellar artery; SCA, superior cerebellar artery; AChA, anterior choroidal artery; PChA, posterior choroidal artery; LStr, lenticulostriates; ThP, thalamoperforators; Sx, microsurgery; E, embolization; NR, no treatment recommended; Dec., declined any treatment; SRS, stereotactic radiosurgery; 2/2, secondary to; Dpress, depression; *denotes unilateral deficit, ie hemianopsia or hemi-paresis/pelgia; PVS, persistent vegetative state; WD, withdrawal of care; bolded cases are illustrated in text. ACCEPTED MANUSCRIPT Table 2: Anatomical distribution of gAVMs in our series. Location No. % 19 Frontal-temporal 4 Parietal 2 Parietal-occipital 11 Parietal-temporal 7 Temporal 3 Temporal-occipital Sylvian 6 3 17 11 4.5 1 1.5 1 1.5 EP Occipital 30 SC Frontal-parietal 8 M AN U 5 TE D Frontal RI PT SUPRATENTORIAL 2 3 2 3 1 1.5 Cerebellar Hemisphere 3 5 Vermian 3 5 64 100 AC C Corpus Callosum Basal Ganglia INFRATENTORIAL TOTAL RI PT ACCEPTED MANUSCRIPT Table 3: Effects of treatment on functional status of patients with gAVMs. mRS 3 – 5 mRS 6 Before Treatment 34 (74%) 12 (26%) 0 After Treatment 13 (28%) 24 (52%) 9 (20%) AC C EP TE D M AN U SC mRS 0 – 2 RI PT ACCEPTED MANUSCRIPT Table 4: Correlation between SM grade, surgical obliteration, and complication rates. SC *Percentage of patients who underwent microsurgical extirpation of AVMs. Microsurgery Complete Obliteration pts.) (%) (%)* III (1) 1 (100) IV (20) 15 (75) V (37) 21 (57) Cerebellar AVM (6) 5 (83) AC C EP TE D M AN U S-M Grade (no. of Complications (%)* 100 0 80 80 90 100 60 100 ACCEPTED MANUSCRIPT conservative management. Complete Obliteration pts. (%) Surgery only 26 20 (77) Embo + Surgery 16 Embolization only Complications (%) Death SC No. of Treatment RI PT Table 5: AVM obliteration rates as well as morbidity and mortality associated with various treatment modalities as compared to (%) 6 (23) 15 (94) 13 (81%) 2 (13) 2 0 2 (100) 1 (50) Embo + SRS 1 0 1 (100) 0 Radiosurgery 1 0 1 (100) 0 No Treatment 18 N/A 16 (89) 5 (28) AC C EP TE D M AN U 25 (96%) AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Key words: Giant arteriovenous malformation, embolization, microsurgery, stereotactic radiosurgery ACA: anterior cerebral artery ACh: anterior choroidal artery AVM: arteriovenous malformation gAVM: giant arteriovenous malformation DSA: digital subtraction angiography SM: Spetzler-Martin grade SRS: stereotactic radiosurgery MRI: magnetic resonance imaging TE D EVD: external ventricular drain M AN U CT: computed tomography HRST: hypofractionated stereotactic radiotherapy ICH: intracranial hemorrhage EP IVH: intraventricular hemorrhage LSt: lenticulostriate artery AC C MCA: middle cerebral artery MRC: medical research council mRS: modified Rankin score NBCA: N-butylcyanoacrylate OR: Odds ratio PCA: posterior cerebral artery SAH: subarachnoid hemorrhage SD: standard deviation SC ARUBA: A Randomized trial of Unruptured Brain AVMs RI PT Abbreviations and Acronyms: ACCEPTED MANUSCRIPT Disclosure Statement: RI PT The authors confirm there are no conflicts of interest or funding sources to disclose. Kevin Reinard, MD Aqueel Pabaney, MD Azam Basheer, MD SC Scott B. Phillips, MD AC C EP TE D M AN U Ghaus M. Malik, MD