Background  Endovascular therapy plays an important role in the treatment of brain arteriovenous malformations (BAVMs). Ethylene vinyl alcohol copolymer (Onyx) is a novel liquid embolic material. This study aimed to summarize our experience of using Onyx for embolization of BAVMs with the focus on embolization technique.
Methods  From September 2003 to November 2007, 115 patients (43 women and 72 men, with a mean age of 29 years) with BAVMs were endovascularly treated with Onyx in our department. The following features of all AVMs were evaluated prior to treatment: type of nidus and shunt, draining veins, and feeding arteries. A total of 196 endovascular procedures were performed.
Results  The course of endovascular treatment was completed in 88 patients. Additional sessions were planned in 27 patients. Of the 88 patients, total occlusion was obtained in 23 patients (26.1%), near-total (>80% of the original volume) occlusion was obtained in 35 patients (39.8%) and partial occlusion (<80% of the original volume) was obtained in 30 patients (34.1%) using embolization as the sole therapeutic technique. Mean volume reduction was 72% (range 30%–100%) in 115 patients. Thirty four patients (38.6%, 34/88) underwent radiosurgical treatment. Additional embolization sessions were planned in 27 patients. Complications occurred in 19 patients (16.5%, 19/115), leading to death in one patient (mortality 0.9%) and permanent disabling in 3 patients (morbidity 2.6%).
Conclusions  Onyx was shown to be feasible and safe for embolization of BAVMs. Proper use of the Onyx injection technique largely improved the endovascular treatment of BAVMs. Large AVMs can be adequately reduced in size through the use of additional treatment.

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The prevalence of brain arteriovenous malformations (BAVMs) has been estimated to be less than 1:100 000. The annual cumulative risk of bleeding is estimated to be 2%–4%, increasing up to 6% in the first year after hemorrhage,¹ with an annual risk of mortality less than 1%.² The treatment of BAVMs has primarily focused on reducing the risk of intracranial bleeding, achieved either by embolization, surgery, radiosurgery, or a combination of these modalities. Endovascular treatment plays a central role in the treatment of BAVMs. The most commonly used embolic agent is the fast polymerizing liquid adhesive n-butyl cyanoacrylate (n-BCA). However, the use of n-BCA remains unpredictable, even in experienced hands. Recently, a novel liquid embolic agent became available: ethylene vinyl alcohol copolymer (Onyx) liquid embolic system (ev3, Irvine, Calif). Onyx is less adhesive and it polymerizes slowly, which seems advantageous over n-BCA.³ The present study reports BAVM embolization techniques using Onyx in 115 patients.

Patients
One hundred and fifteen patients with BAVM were embolized with Onyx between September 2003 and November 2007. BAVM was confirmed in all patients by brain imaging and conventional cerebral angiography. The following features of all AVMs were evaluated prior to treatment: type of nidus and shunt, draining veins, and feeding arteries. Other types of intracranial fistulas (such as dural arteriovenous fistulas, vein of Galen type malformations) were not included. The study comprised a total of 43 women and 72 men ranging in age from 5 to 56 years old (a mean age of 29 years). Clinical presentation included AVM hemorrhage in 43 patients (37.4%), subarachnoid hemorrhage from concomitant aneurysm in two patients (1.7%), seizures in 34 patients (29.6%), headache in 21 patients (18.3%), nonhemorrhagic focal neurological deficit in 12 patients (10.4%), and in three patients (2.6%) the AVM was incidentally discovered.

Classification and localization of BAVMs
BAVMs were classified according to the Spetzler-Martin classification (Table 1). Seven AVMs (6.1%) were located in the cerebellum, and 17 (14.8%) were located in the deep brain (nine in the corpus callosum, seven in the basal ganglia and one in the brain stem). The locations of the remaining 91 AVMs were — in order of decreased frequency — temporal (24, 20.9%), parietal (17, 14.8%), occipital (13, 11.3%), fronto-parietal (13, 11.3%), frontal (7, 6.1%), frontotemporal (5, 4.3%), temporal-parietal (5, 4.3%), temporal-occipital (4, 3.5%), parieto-occipital (2, 1.7%) and fronto-temporo-parietal (1, 0.9%). The maximum BAVM diameter was <2 cm in 15 patients (13%), 2–4 cm in 53 patients (46.1%), 4–6 cm in 32 (27.8%) patients, and >6 cm in 15 patients (13.0%).

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Table 1. Characteristics of BAVMs in 115 patients

Onyx liquid embolic agent
The endovascular treatment of intracranial AVMs using the copolymer ethylene vinyl alcohol was first described in 1990.^4,5 Ethylene vinyl alcohol (EVOH) has been commercially available in Europe since 1999 as the non-adhesive liquid embolic systems Onyx 18, Onyx 20, and Onyx 34. Onyx 18 and Onyx 34 were approved by the United States Food and Drug Administration in July 2005. The numbers 18, 20, and 34 represent the viscosity in centipoise. Tantalum powder is added to the mixture for radiopacity. The Onyx solution must, therefore, be shaken for at least 20 minutes prior to injection to achieve homogeneous radiopacity of the mixture.⁶ The Onyx solution is dissolved in dimethylsulfoxide (DMSO) for injection, and DMSO has potentially angiotoxic effects. However, these are negligible if the recommended infusion rates are used.⁷ Polymer precipitation upon contact with aqueous solution results in a soft, non-adherent mass that is capable of producing permanent vascular occlusion.⁸

Embolization procedure
All procedures were carried out under general anesthesia without systemic heparinization. During the procedure, systolic blood pressure was controlled between 100 and 110 mmHg. Catheterization was performed using a transfemoral approach with standard coaxial techniques. The guiding catheter was flushed via a pressure bag with saline containing 2500 U heparin/L. Navigation of a DMSO-compatible microcatheter (UltraFlow or Marathon; ev3; USA) to the target was performed with a combination of the flow-guided and wire-guided techniques using a 0.010-inch or a 0.008-inch wire (Silverspeed or Mirage; ev3; USA). Once the microcatheter tip was in the desired position, the injection of Onyx was carried out as follows: 1) the microcatheter was flushed with 5 ml normal saline; 2) 0.25 ml DMSO was injected into the microcatheter to fill the dead space; 3) Onyx was aspirated into a 1 ml syringe, and 0.25 ml of this amount was injected over for 40 seconds to fill the microcatheter and to replace the DMSO in the dead space; 4) slow injection of the Onyx was then continued under fluoroscopy.

Based on our previous experiences of BAVM embolization with Onyx, the following tips were compiled. (1) The feeding pedicle selection and access status of the microcatheter are not only essential for reflux control, but are critical for the embolization effect. The primary nidus supply should be selected, normal branches should be avoided and microcatheter access the nidus should be aided by guide wire. (2) Although a single injections of Onyx can be performed over 75 minutes (extened injection time is possible due to the less adhesive nature of Onyx), it is advised to control the Onyx injection time through a single feeding artery to within 30–40 minutes. During injections, the injection speed should be adjusted from time to time according to penetration speed and direction as well as reflux conditions. The procedure can be temporarily paused to obtain an angiogram for assessment of nidus occlusion and the status of draining veins. Onyx then fills a different portion of the nidus, with no further reflux or filling of the vein. It should be attempted to control reflux length of Onyx to <2.0 cm, or between 0.5–1.0 cm in case of circuitous blood vessels. (3) Onyx reflux via the nidus into a remote feeder of the AVM may lead to complications, which was consistent with our observations. When reflux is detected by fluoroscopy, injection is immediately stopped. However, if the feeding pedicle is falsely interpreted as part of the nidus, infarction in the vascular territory of the feeding pedicle may occur. It is, therefore recommend to use biplane fluoroscopy during Onyx injection or frequent changes in the angle of the x-ray tube. (4) In case diffusion towards normal arteries occurs, the injection should be stoped and new trend observed, rather than withdrawing the catheter and terminating the procedure. As long as the normal branches, together with the distal vessels are not completely occluded, remnants of Onyx in normal arteries will not lead to corresponding nerve disfunction. Therefore, a comprehensive understanding of nidus angioarchitecture prior to and during procedure is quite important. (5) For microcatheter withdrawal, gently stretch it up and pull out rapidly. However, for cases where the injection time is extended, or where reflux is severe, it is better to terminate the procedure to avoid blood vessel rupture and bleeding.

Postembolization care
After embolization, patient blood pressure was strictly monitored for 48 hours in the intensive care unit. In rare event the microcatheter sticking in the arterial feeder, heparin was intravenously administered (750–1000 U/hour) for 72 hours, follow by oral aspirin for 3 months at a dose of 250 mg/d. For the majority BAVMs, the goal was to reduce the BAVM nidus size to the point where radiosurgery would be possible, preferably with one embolization session. In some cases, where complete nidus occlusion was likely, Onyx was allowed to occlude the proximal parts of the draining veins at the end of the procedure. If, after the patient has completed one or more embolization sessions, the remaining largest diameter of the nidus is <3.0 cm, concomitant aneurysm is excluded by embolization and the brain AVM is located in an eloquent area, or when a deep venous drainage is evident, radiosurgery is then planned. After radiosurgery, the follow-up consisted of yearly MRI. When MRI suggested complete obliteration of the nidus, angiography was performed to confirm or refute this finding. When the AVM was not obliterated after two years, MRI was repeated one year later. If after three years the AVM was still not obliterated, repeated radiosurgery was considered.

A total of 115 patients with brain AVMs were treated by endovascular embolization alone or in combination with radiosurgery. A total of 196 embolization procedures were performed with a mean of 1.7 procedures (range 1–5) per patient: 68 patients underwent one procedure; 21 underwent two procedures; 19 underwent three procedures; 6 underwent four procedures; and 1 underwent five procedures. In 175 (89.3%) of the embolization sessions, Onyx 18 was used (reduced dense version that offers better nidus penetration) as the sole embolic material; in 15 (7.6%) sessions Onyx 18 and n-BCA was used; in 6 (3.1%) sessions, Onyx 34 was used in the embolization of direct fistulas; in 3 cases (1.5%) of AVMs accompanied by feeder aneurysms, a detachable coil was employed to occlude the aneurysms.

Occlusion rate
An average of 72% (range 30%–100%) estimated size reduction was achieved in 115 patients. In a total of 88 patients (76.5%, 88/115), treatment was completed, total AVM occlusion was achieved by embolization alone in 23 (26.1%, 23/88), near-total occlusion (>80% of the original volume) was achieved in 35 (39.8%, 35/88) and partial occlusion (<80% of the original volume) was obtained in 30 (34.1%) patients by using embolization as the sole therapeutic technique. Total obliteration was confirmed at follow-up angiograms after 12–24 weeks. After the endovascular treatment was accomplished and the nidal size was reduced to <3 cm, thirty four (38.6%, 34/88) patients underwent radiosurgical treatment. In the 34 patients treated with adjunctive embolization and radiosurgery, follow-up angiography showed complete obiliteration after radiosurgery in 10 patients. The remaining 24 patients are awaiting 2-year postradiosurgery results. More embolization sessions were planned in 27 patients.

Complications
Complications were categorized as follows: non-neurologic complications (such as catheter stuck without clinical consequences), transient neurologic complications (defined as new neurologic deficits that resolved completely within seven days), permanent non-disabling deficits, permanent disabling deficits, and death. After a total of 196 procedures in 115 patients, neurologic status remained unchanged or improved in 96 (83.5%) patients. Treatment-related complications were observed in 19 patients (16.5%), among whom, 15 present with unruptured AVMS and 4 with ruptured AVMS prior to embolization. Patients initially presented with intracranial hemorrhage exhibited a low embolization risk, or inversely, patients who had not bled before had a higher risk of new embolization-related deficits (Table 2).

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Table 2. Summary of embolization-related complications (n (%))

In five patients, a microcatheter was glued in the AVM and cut off in the groin because of the long injection time and reflux length. Of these five patients, three exhibited no new neurologicl deficit, one patient with transient diplopia, and another patient with transient right hemiparesis. Sixteen patients (13.9%) exhibited a new focal neurological deficit (hemiparesis, limb paresis, aphasia or visual disturbances) during the immediate post-operative period. The deficit was transient in 10 cases (8.7%). Of the permanent deficits, three out of five were ischemic (2.6%) and two were hemorrhagic (1.7%). The deficit was disabling in three patients. According to the modified Rankin Scale (mRS),^9,10 two patients were rated at mRS 5, and one patient with mRS 4 after the 2-year follow-up. One patient (0.9%) died in this series.

To date, n-BCA has been the most frequently used embolic agent for BAVM embolization. Complete endovascular obliteration rates with n-BCA vary in the literature but has been estimated in the range of 10%.¹¹ Onyx is a newer polymerizing agent consisting of EVOH dissolved in DMSO and mixed with micronized tantalum powder for radiopaque visualization.¹² Our initial experience with Onyx for BAVM embolization has been encouraging, with an average size reduction of 72% and complete obliteration with embolization alone in 26.1% of cases. In most patients, one embolization session was sufficient to obtain complete obliteration or sufficient size reduction for subsequent radiosurgery. These results are comparable to other studies that have used Onyx.^3,13-19

In contrast to n-BCA, Onyx is a less adhesive liquid.^14,16,17 This basic characteristic eliminates the risk of gluing the catheter to the vessel wall and therefore allows an extended injection time and a wider range of varying injection rates. Both facilitate the occluding of larger nidus portions for each injection.³ However, despite this advantage, a microcatheter can be trapped within the feeding pedicle during Onyx injection, in particularly during long injections, when there is a large amount of reflux or the feeding pedicle represents a very distal and tortuous loop.¹⁶ During initial use with Onyx, six microcatheter ruptures occurred. All ruptures took place when the microcatheter was pulled out of the catheterized feeding pedicle. However, in contrast to previous reports,³ no clinical side effects occurred. By adjusting the technique to the above-mentioned factors, it has been possible to avoid trapping of the microcatheter during the last two years. The microcatheter was rarely be glued to the nidus, which occurred in five of 196 injections during initial trials, because more reflux was tolerated to treat large AVMs. Since November 2005, most likely because of better reflux control, no microcatheter trapping has occurred.

The principle of AVM occlusion therapy that was adopted for the present study was primarily to improve symptom and reduce the risk of subsequent bleeding, while avoiding overly increased occlusion rate (Figure). Although Onyx allows for better filling of BAVM nidus than n-BCA, results from the present study suggested staged embolization sessions to reduce peri-procedural complications. Therefore, even if nidus catheterization can be accomplished through more than one feeder, staged occlusion of the BAVM is preferred over several sessions, regardless of whether Onyx fully penetrate a nidus even in large BAVMs. This strategy has also been adopted in another study.¹⁶ According to results from the present study, this approach also reduces the risk of ischemic complications and microcatheter trapping. When the nidus is not completely obliterated with patent draining veins, stagnant flow might result in thrombosis of these veins, leaving a section of the nidus without drainage. This situation could lead to a post-embolization hemorrhage, which occurred in three from the present study.

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Figure. A 6-year-old boy with right cerebellar AVM, embolized with Onyx. Anteroposterior view of right vertebral angiograms (A) and lateral view of right vertebral angiograms (B) showed that AVM was fed by superior cerebellar artery and anterior inferior cerebellar artery; angiograms obtained after embolization (C and D) showed substantial reduction of the nidus and arteriovenous shunting. Anteroposterior projection (E) and lateral projection (F) showed the Onyx cast in the malformation.

The present complication rate of 16.5% was consistent with other studies that used Onyx, n-BCA, or particles as embolic agents.^1,3,20,21 The majority of complications resulted in transient morbidity, however, and the ultimate permanent morbidity and mortality rates were relatively low compared to earlier series. Results demonstrated a clinically significant complication rate of 16.5% (9.6% per procedure) and a mortality rate of 0.9%.

With regard to natural disease course, the present study was comparable to previous syudys.^3,13 Surgical handling of Onyx solution was determined to be superior to n-BCA in a swine model,²² according to histopathological results.²³ Embolization of intracranial AVMs with the Onyx system allowed for targeted reduction of the intranidal AVM and, in most patients, preventd venous embolization and accompanying damage to perinidal brain-supplying arteries. The accumulation of a liquid embolic agent into nidal draining veins is an important risk factor for complications following AVM embolization.²⁴ With the use of Onyx embolic system, glue accumulation can easily be prevented by terminating the injection procedure.¹⁴ From a neurosurgical perspective, pure arterial ligation by embolization with n-BCA allows the nidus to remain compressible during AVM resection.²⁴ This treatment goal was applicable for the Onyx embolic system as well. Intranidal embolization with the Onyx system results in a compact, soft and spongiform tumor-like mass in the AVM. The embolized vessels are completely filled with the embolic agent. The operating neurosurgeon described the embolized vessels as less fragile, possibly due to decreased inflammatory and the absence of polymerization heat, compared with n-BCA-embolized AVMs. Therefore, exact identification of the AVM margins, in particular the eloquent regions, was possible. In fact, centrally located, large AVMs can be reseted precisely by endovascular treatment with Onyx.

Initial results obtained using the Onyx system for endovascular treatment of cerebral AVMs have been reported from single and multi-center studies.^3,6,13-19 The results have been promising, including establishment of extended-duration injections and improved angiographic outcomes. Although a good outcome could be attained in the majority of patients, correct embolization technique is mandatory to avoid complications.

In our experience, Onyx has been a promising embolic agent for BAVM embolization, and proved feasible and safe to use for brain AVMs. A good command of Onyx injection technique could largely improve the endovascular treatment of brain AVMs. Large AVMs can be adequately reduced in size through the use of additional treatment. Further studies are needed to evaluate the long-term efficacy of this treatment and to compare it with more traditional endovascular therapies.

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3. Jahan R, Murayama Y, Gobin YP, Duckwiler GR, Vinters HV, Viñuela F. Embolization of arteriovenous malformations with Onyx: clinicopathological experience in 23 patients. Neurosurgery 2001; 48: 984-995.

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12. Alexander MJ, Tolbert ME. Targeting cerebral arteriovenous malformations for minimally invasive therapy. Neurosurgery 2006; 59 (5 Suppl 3): s178-s183; discussion s3-s13.

13. Hamada J, Kai Y, Morioka M, Kazekawa K, Ishimaru Y, Iwata H, et al. A mixture of ethylene vinyl alcohol copolymer and ethanol yielding a nonadhesive liquid embolic agent to treat cerebral arteriovenous malformations: initial clinical experience. J Neurosurg 2002; 97: 881-888.

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