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Published online before print September 24, 2001, 10.1148/radiol.2212001140
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(Radiology. 2001;221:309-317.)
© RSNA, 2001

Neuroradiology

Head and Neck Hypervascular Lesions: Embolization with Ethylene Vinyl Alcohol Copolymer—Laboratory Evaluation in Swine and Clinical Evaluation in Humans1

Y. Pierre Gobin, MD, Yuichi Murayama, MD, Karen Milanese, MS, Kira Chow, MD, Nestor R. Gonzalez, MD, Gary R. Duckwiler, MD and Fernando Viñuela, MD

1 From the Department of Radiological Sciences, UCLA Medical Center, Los Angeles, Calif. Received June 26, 2000; revision requested July 27; final revision received March 28, 2001; accepted April 9. Address correspondence to Y.P.G., Department of Radiology, New York Hospital, 525 East 68th St, New York, NY.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: (a) To assess in swine long-term (12-month) histopathologic changes, particularly, those related to recanalization and angiotoxicity after endovascular delivery of ethylene vinyl alcohol copolymer (EVAC), and (b) to evaluate initial clinical experience in 18 patients with head and neck tumors and arteriovenous malformations.

MATERIALS AND METHODS: Embolization with EVAC was performed in one rete each in five swine. After 12 months, an angiogram was obtained, and the contralateral rete was also embolized (acute). Swine were sacrificed and the retia harvested for pathologic examination. In the clinical study, 18 patients with tumors (n = 14), facial arteriovenous malformations (n = 3), and vertebral arteriovenous fistula (n = 1) underwent therapeutic embolization. The technical aspects of EVAC embolization, percentage of occlusion, and clinical complications were evaluated.

RESULTS: Angiographic 12-month follow-up in swine revealed persistent occlusion of the embolized rete or retia. Histologic examination of the same rete showed vascular occlusion and moderate intraluminal foreign body giant cell reaction; the acutely embolized rete showed no endothelial denudation or angionecrosis. Clinical evaluation in patients revealed satisfactory penetration of lesion vasculature with EVAC when the microcatheter was advanced within 2 cm of a lesion or when percutaneous puncture was performed. There were two transient complications: one increase in a preexisting fifth nerve palsy and one increase in preexisting hemiparesis.

CONCLUSION: EVAC is a promising liquid embolic material providing long-term occlusion of blood vessels.

Index terms: Arteries, therapeutic embolization, 9*.1264 • Arteriovenous malformations, therapeutic embolization, 9*.12642, 18.1264, 28.1264 • Embolism, experimental studies • Head and neck neoplasms, therapy, 18.1264, 28.1264


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Embolization of hypervascular tumors and arteriovenous malformations (AVMs) in the head and neck is a well-established therapeutic modality. Preoperative embolization reduces intraoperative blood loss, shortens surgical time, and decreases surgical morbidity and mortality (1–5). Furthermore, intraoperative hemorrhage renders the complete resection of a lesion more difficult, which increases the risk of recurrence (6–8). Embolization as the sole treatment of AVM can be either curative or palliative for symptoms such as pain or mass effect (5,9,10). Depending on the angioarchitecture of the lesion, embolization can be performed with a variety of embolic materials including particles, liquid agents, or mechanical devices. Each embolic agent has specific strengths and weaknesses. Of the commonly used embolic agents, liquid agents, such as N-butyl-cyanoacrylate, have the best combination of penetration and permanence. However, embolization with cyanoacrylate is difficult because precise delivery is not totally controllable. Moreover, cyanoacrylate is a bioadhesive and may glue a catheter in place (11–13). To overcome the limitations of cyanoacrylate, safer liquid embolic agents are in development.

In this paper we report animal and clinical studies of ethylene vinyl alcohol copolymer (EVAC), a nonadhesive radiopaque liquid embolic agent. The purposes of this study were (a) to assess the long-term (12 months) histopathologic changes, particularly those related to recanalization and angiotoxicity after endovascular delivery of EVAC and its organic solvent dimethyl sulfoxide (DMSO), and (b) to report our initial clinical experience in 18 patients with head and neck tumors and AVMs.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
EVAC
The chemical formula of EVAC is closely related to ethyl vinyl alcohol described by Taki et al (14). The embolic agent (Onyx; Micro Therapeutics, San Clemente, Calif) is EVAC (48 moles per liter ethylene and 52 moles per liter vinyl alcohol) dissolved in DMSO. The solution is made radiopaque by the addition of micronized tantalum powder. When placed in aqueous solutions, such as blood, the DMSO diffuses out causing precipitation of the copolymer and formation of a spongy embolus in situ, which does not adhere to the vascular wall or delivery catheter. The EVAC agent is available in concentrations ranging from 6% copolymer dissolved in 94% DMSO to 20% copolymer dissolved in 80% DMSO. The smaller the concentration of copolymer, the more fluid the agent and the more distal the vascular penetration. At the time of this study, EVAC was available in three concentrations: 6%, 6.5%, and 8%.

Embolization Technique
Vials of EVAC were placed in a shaker (Vortex-Genie; Micro Therapeutics) for 20 minutes to mix the components. Two DMSO-compatible microcatheters, a guide- wire–directed 2.2-F microcatheter and a flow-directed 1.8-F microcatheter (Easy Rider and Flow Rider; Micro Therapeutics), were used. Once the microcatheter was appropriately positioned, it was flushed with 3 mL of saline, and the dead space of the microcatheter was filled with 0.25 mL of DMSO. The EVAC was aspirated in a DMSO-compatible 1-mL syringe (Luer-lok, Micro Therapeutics). The first 0.25 mL of EVAC were injected through the microcatheter within 50 seconds to fill the dead space of the microcatheter with EVAC, while slowly flushing the DMSO to avoid angiotoxic effects, which have been related to fast injections (15). Finally, EVAC was injected with fluoroscopic control into the vasculature until the desired penetration was achieved.

Laboratory Study
All experiments were conducted in accordance with the regulations set by the University Chancellor Animal Research Committee and National Institutes of Health guidelines. Five Yorkshire cross swine (S and S, San Diego, Calif) were used in this study. The swine were aged 3–4-months, 30–40 kg, mixed sex, and maintained on a standard laboratory diet. After an overnight fast, each animal was premedicated intramuscularly with 20 mg per kilogram of body weight of ketamine (Fort Dodge Animal Health, Fort Dodge, Iowa) and 2 mg/kg xylazine (Bayer, Shawnee, Kan). During the procedure, general anesthesia was maintained with mechanical ventilation and inhalation of 1%–2% halothane after endotracheal intubation.

The swine rete mirabile (or rete) was previously used for the evaluation of numerous embolic agents (16–18). The rete is a thin arterial netting, which in swine replaces the intracavernous segment of the internal carotid artery and is well suited for the study of embolization materials (Fig 1). By using a transfemoral approach, a 6-F guiding catheter was positioned in the common carotid artery. An intraarterial bolus of 3,000 U of heparin was injected. A DMSO-compatible microcatheter was positioned coaxially through the guiding catheter, with its tip positioned in the ascending pharyngeal artery proximal to the rete. After superselective angiography and with fluoroscopic guidance, EVAC was delivered as explained in the previous section, either until occlusion of the proximal half of the rete was obtained or until reflux into the ascending pharyngeal artery was observed. The following factors were evaluated during embolization: amount of EVAC injected, injection time, fluoroscopic visualization of EVAC, rheologic characteristics of EVAC, and ease of microcatheter withdrawal after embolization. Following embolization, the animals were kept alive for 12 months and checked regularly. After 12 months, postembolization angiography was performed to evaluate the permanence of occlusion. The contralateral rete was embolized with EVAC as described. The swine were then immediately euthanized according to laboratory protocol. The retia were surgically removed and fixed in 10% formalin. Sections were stained with hematoxylin-eosin and elastica van Gieson for microscopic evaluation of acute and chronic inflammatory response to the embolic material, focusing on the presence of angionecrosis, hemorrhage, or extravasation.



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  		Figure 1a. (a) Left anteroposterior carotid angiogram in a swine shows left rete mirabile (thick arrow) interposed between the ascending pharyngeal artery (arrowhead) and the intracranial internal carotid artery (thin arrow). A DMSO-compatible microcatheter was selectively placed in the ascending pharyngeal artery, and embolization was performed with 6% EVAC. (b) Left anteroposterior carotid angiogram 1 year after embolization shows persistent total occlusion of rete mirabile, with thrombosis of the ascending pharyngeal artery (arrowhead).

 


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  		Figure 1b. (a) Left anteroposterior carotid angiogram in a swine shows left rete mirabile (thick arrow) interposed between the ascending pharyngeal artery (arrowhead) and the intracranial internal carotid artery (thin arrow). A DMSO-compatible microcatheter was selectively placed in the ascending pharyngeal artery, and embolization was performed with 6% EVAC. (b) Left anteroposterior carotid angiogram 1 year after embolization shows persistent total occlusion of rete mirabile, with thrombosis of the ascending pharyngeal artery (arrowhead).

 
Clinical Evaluation
Forty-eight consecutive patients with hypervascular head and neck lesions underwent angiography between July 1998 and July 1999. Of these 48 patients, 18 were enrolled in this study. The inclusion criteria were (a) patient informed consent, (b) an initial angiogram that confirmed the lesion was hypervascular, and (c) selective microcatheterization was possible. Major exclusion criteria were the inability to give informed consent and pregnancy. Another exclusion criterion (after patient 6 experienced cranial nerve paresis) was the embolization of vessels potentially supplying cranial nerves. All patients were treated in accordance with the policies set by our institution medical internal review board and Food and Drug Administration regulations.

These 18 patients had 14 tumors (eight meningiomas, four carotid paragangliomas, one carotid schwannoma, one skull hemangioma) and four vascular malformations (three facial AVMs and one direct vertebral arteriovenous fistula). There were eight men and 10 women, with a mean age of 45 years (range, 4–74 years). Eight patients presented with headache, three with palpable mass, two with cranial nerve palsy, two with confusion, one with gait ataxia, one with sensory deficit, and one with aphasia. Lesion locations are listed in the Table.


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  		Results of EVAC Embolization Clinical Study

 
All patients underwent general anesthesia for the embolization procedure. Every procedure was performed by one of three senior interventional neuroradiologists (Y.P.G., F.V., G.R.D.) at our institution. Before treatment, complete diagnostic cerebral angiography was performed, which included superselective injections, to confirm the hypervascularity of the lesion and to more precisely define angiographic anatomy; lesion volumes, arterial feeders, and blush were evaluated.

In 17 patients, systemic anticoagulation was performed by using an initial bolus of 2,000–3,000 U of heparin, followed by continuous infusion of 1,000 U/h. One case (case 11), exclusively treated with direct percutaneous puncture embolization, did not receive heparin. By using a transfemoral approach, a 6-F guiding catheter was positioned in the common carotid artery. Selective catheterization of feeding arteries was performed by using a 2.2-F DMSO-compatible microcatheter (Easy Rider; Micro Therapeutics). In three cases, vascular access was percutaneously obtained with fluoroscopic guidance and roadmapping technique. A 21-gauge needle was directed into the tumor or AVM until there was brisk reflux of blood through the needle. Contrast material was then injected to judge if the needle position was appropriate (ie, adequate visualization of tumor vascularity or AVM nidus). Embolization, by using the technique explained, was performed until the desired occlusion of the abnormal vessels was achieved. Data on tumor volume (estimated by means of the angiographic measurement of three diameters [anteroposterior, transverse, craniocaudal] divided by 2), intensity of blush, and EVAC concentration were recorded. After the embolization procedure, global angiograms were obtained to assess postembolization lesion volume and percentage of lesion embolization according to the following formula: [(volume before embolization - volume after embolization)/volume before embolization] x 100. Interventional neuroradiologists (G.R.D., F.V., Y.P.G.) assessed various characteristics of EVAC: fluoroscopic visibility, injectability, control of EVAC placement, and degree of EVAC penetration into the vasculature.

After the embolization procedure, patients were observed for a minimum of 12 hours in a neurology intensive care unit and assessed for the development of new symptoms. In 14 cases, surgery was performed within 24 hours. One patient was taken directly to surgery after the embolization procedure. In three AVM cases, surgery was not performed. Postoperatively, surgeons documented type of resection, estimated intraoperative blood loss, and amount of blood transfused.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Laboratory Study
All rete and ascending pharyngeal arteries were occluded successfully. Injections of 0.3–0.5 mL of EVAC were performed over 20–40 seconds. The EVAC did not occlude any microcatheters. The density of the embolic material was homogeneous throughout the injection and was well depicted at fluoroscopy. EVAC did not fragment; it formed a single radiopaque column that was pushed progressively with fluoroscopic guidance until the embolic material either penetrated the proximal half of the rete or refluxed around the microcatheter. No difficulty was encountered withdrawing the microcatheter after embolization. No detectable adverse effects or deaths occurred after embolization, and the five animals survived 12 months without complication. Control angiography performed after 12 months revealed total occlusion of the five retia, without evidence of recanalization (Fig 1).

Histologic examination of the five retia that were embolized immediately prior to sacrifice depicted complete occlusion of the rete vessels by the embolic material, without evidence of endothelial denudation or angionecrosis. Embolic material remained in the lumina and penetrated arteries as small as 250–400 µm. There was no evidence of acute cellular inflammatory response or hemorrhage in the perivascular space (Fig 2a).



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  		Figure 2a. Embolization of swine rete mirabile. (a) Photomicrograph of acute embolization by using EVAC (black aggregates) shows occlusion of the arterial lumen, without signs of arterial wall necrosis, acute inflammatory response, or extravasation of the material. (Hematoxylin-eosin stain; original magnification, x4). (b) Photomicrograph of chronic embolization (12 months) by using EVAC (black aggregates) shows complete occlusion of rete vessels and the presence of an organized thrombus (arrow). Surrounding the embolic material there is a moderate intrawall and intraluminal foreign body giant-cell reaction (a marker of a moderate inflammatory process). Although there is some disruption of the elastica in the arterial wall, there are no signs of angionecrosis or extravasation of embolic material, (Hematoxylin-eosin stain; original magnification, x10.)

 


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  		Figure 2b. Embolization of swine rete mirabile. (a) Photomicrograph of acute embolization by using EVAC (black aggregates) shows occlusion of the arterial lumen, without signs of arterial wall necrosis, acute inflammatory response, or extravasation of the material. (Hematoxylin-eosin stain; original magnification, x4). (b) Photomicrograph of chronic embolization (12 months) by using EVAC (black aggregates) shows complete occlusion of rete vessels and the presence of an organized thrombus (arrow). Surrounding the embolic material there is a moderate intrawall and intraluminal foreign body giant-cell reaction (a marker of a moderate inflammatory process). Although there is some disruption of the elastica in the arterial wall, there are no signs of angionecrosis or extravasation of embolic material, (Hematoxylin-eosin stain; original magnification, x10.)

 
Histologic examination of the five retia 12 months after embolization revealed occlusion of rete vessels by dense aggregates of black particulate material and a moderate intraluminal foreign body giant-cell reaction. Disruption of the elastica was observed in four retia, and focal intimal hyperplasia occurred in two retia. Thrombi, generally well organized, were present in four retia with early calcification in one. Negligible recanalization was observed in one rete. No eosinophilic activity to indicate allergic reaction was observed. No blood products (eg, hemosiderin or hematoidin) indicating hemorrhage were revealed in the extravascular space. No angionecrosis or extravasation of embolic material was observed, although, embolic material was observed in the vessel wall in four cases and in the vascular adventitia in three cases (Fig 2b).

Clinical Investigation
Selective catheterization of external and internal carotid artery branches was performed in all patients and direct percutaneous puncture in cases 11, 13, and 16. Preembolization lesion volume, blush, and arterial feeders are listed in the Table. Embolization was performed by using EVAC in 17 arterial feeders (Table). A 6% EVAC agent was used for tumor embolization, and 6%, 6.5%, and 8% EVAC for AVM and fistula embolization. The volume of EVAC injected was 0.2–1.0 mL per embolization and duration of injection was 20–40 seconds. In cases 11, 13, and 16, the lesions were accessed by direct percutaneous puncture. Additional embolic materials (coils or polyvinyl alcohol particles) were used as needed in five patients. Coils were used in three patients. In case 6 (meningioma), coils were used to occlude the orbital branch of the middle meningeal artery before more proximal EVAC embolization. In case 8 (meningioma), coils were used to occlude meningeal branches arising from the internal carotid artery (inferolateral trunk and meningohypophyseal artery), as these arteries were deemed unsafe for EVAC or polyvinyl alcohol particle embolization. In case 17 (vertebral arteriovenous fistula), multiple Guglielmi detachable coils and fibered detachable coils were deployed from the venous side of the arteriovenous fistula to the vertebral artery distal to the fistula to slow the flow before EVAC injection. In case 11 (frontal bone hemangioma), after most of the tumor was embolized with EVAC delivered by direct percutaneous puncture, devascularization was completed with polyvinyl alcohol particle embolization of bilateral anterior branches of the superficial temporal artery. In cases 13 and 16 (facial AVMs), EVAC embolization was performed with a combination of superselective arterial catheterization and by direct percutaneous puncture. Locations of embolization, embolic materials (EVAC, polyvinyl alcohol particles, or coils), postembolization angiographic results, and postembolization complications are listed in the Table. Angiographic reduction of the tumor blush was more than 90% in 10 cases, 70%–89% in three, 50%–69% in three, and less than 50% in two.

During embolization, EVAC was well depicted with subtracted fluoroscopy. During embolization of low-flow (tumors) and high-flow (AVMs) arterial feeders, EVAC formed a single column that did not fragment. During embolization of low-flow arterial feeders in tumors with 6% EVAC, good filling of the tumor vessels was seen in 6 of (43%) 14 cases, when the microcatheter could be advanced to within 2 cm of tumor vessels (Figs 3, 4) or when direct puncture was performed. In AVMs, some penetration of the nidus was achieved in all cases; however, the best nidus penetration was achieved with direct percutaneous puncture embolization (Fig 5). No catheter was glued in place, even when EVAC refluxed around the microcatheter tip. In one case, it was initially difficult to remove the microcatheter, but after approximately 10 minutes the microcatheter was removed without incident. This difficulty was attributed to vasospasm.



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  		Figure 3a. Embolization of a left convexity meningioma. (a) Lateral angiogram of left external carotid artery shows tumor blush (solid arrows) of left convexity meningioma vascularized by the left middle meningeal artery (open arrow). (b) Selective lateral angiogram of left middle meningeal artery before embolization. (c) Unsubtracted lateral angiogram after embolization with 6% EVAC shows mild penetration of EVAC into tumor arteries (small arrows). The main trunk of the middle meningeal artery (large arrow) is blocked with EVAC.

 


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  		Figure 3b. Embolization of a left convexity meningioma. (a) Lateral angiogram of left external carotid artery shows tumor blush (solid arrows) of left convexity meningioma vascularized by the left middle meningeal artery (open arrow). (b) Selective lateral angiogram of left middle meningeal artery before embolization. (c) Unsubtracted lateral angiogram after embolization with 6% EVAC shows mild penetration of EVAC into tumor arteries (small arrows). The main trunk of the middle meningeal artery (large arrow) is blocked with EVAC.

 


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  		Figure 3c. Embolization of a left convexity meningioma. (a) Lateral angiogram of left external carotid artery shows tumor blush (solid arrows) of left convexity meningioma vascularized by the left middle meningeal artery (open arrow). (b) Selective lateral angiogram of left middle meningeal artery before embolization. (c) Unsubtracted lateral angiogram after embolization with 6% EVAC shows mild penetration of EVAC into tumor arteries (small arrows). The main trunk of the middle meningeal artery (large arrow) is blocked with EVAC.

 


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  		Figure 4a. Embolization of a carotid body paraganglioma. (a) Lateral angiogram of external carotid artery shows the intense tumor blush (arrows) of carotid body paraganglioma. (b) Selective lateral angiogram of a descending branch of the ascending pharyngeal artery before embolization. Arrow indicates the tip of a DMSO-compatible microcatheter. (c) Unsubtracted lateral angiogram after embolization with 6% EVAC shows that embolic material filled the main tumor arteries (white arrows) and a draining vein (black arrow). (d) Lateral angiogram of common carotid artery after embolization of the ascending pharyngeal artery. Note the presence of radiopaque EVAC (black arrow) in the tumor and residual blush (white arrow) in the inferior part of the tumor.

 


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  		Figure 4b. Embolization of a carotid body paraganglioma. (a) Lateral angiogram of external carotid artery shows the intense tumor blush (arrows) of carotid body paraganglioma. (b) Selective lateral angiogram of a descending branch of the ascending pharyngeal artery before embolization. Arrow indicates the tip of a DMSO-compatible microcatheter. (c) Unsubtracted lateral angiogram after embolization with 6% EVAC shows that embolic material filled the main tumor arteries (white arrows) and a draining vein (black arrow). (d) Lateral angiogram of common carotid artery after embolization of the ascending pharyngeal artery. Note the presence of radiopaque EVAC (black arrow) in the tumor and residual blush (white arrow) in the inferior part of the tumor.

 


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  		Figure 4c. Embolization of a carotid body paraganglioma. (a) Lateral angiogram of external carotid artery shows the intense tumor blush (arrows) of carotid body paraganglioma. (b) Selective lateral angiogram of a descending branch of the ascending pharyngeal artery before embolization. Arrow indicates the tip of a DMSO-compatible microcatheter. (c) Unsubtracted lateral angiogram after embolization with 6% EVAC shows that embolic material filled the main tumor arteries (white arrows) and a draining vein (black arrow). (d) Lateral angiogram of common carotid artery after embolization of the ascending pharyngeal artery. Note the presence of radiopaque EVAC (black arrow) in the tumor and residual blush (white arrow) in the inferior part of the tumor.

 


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  		Figure 4d. Embolization of a carotid body paraganglioma. (a) Lateral angiogram of external carotid artery shows the intense tumor blush (arrows) of carotid body paraganglioma. (b) Selective lateral angiogram of a descending branch of the ascending pharyngeal artery before embolization. Arrow indicates the tip of a DMSO-compatible microcatheter. (c) Unsubtracted lateral angiogram after embolization with 6% EVAC shows that embolic material filled the main tumor arteries (white arrows) and a draining vein (black arrow). (d) Lateral angiogram of common carotid artery after embolization of the ascending pharyngeal artery. Note the presence of radiopaque EVAC (black arrow) in the tumor and residual blush (white arrow) in the inferior part of the tumor.

 


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  		Figure 5a. Embolization of a large facial AVM in a 4-year-old child with intractable oral hemorrhage. (a) Lateral angiogram of left external carotid artery shows mandibular (arrows) and maxillary (arrowheads) portions of facial AVM. (b) Unsubtracted lateral angiogram during embolization with 8% EVAC by means of direct puncture into the mandible with a 21-gauge needle. (c) Unsubtracted lateral angiogram after embolization, showing the cast of EVAC in the mandibular AVM (arrows). (d) Lateral angiogram of left external carotid artery after embolization shows good flow reduction in the AVM. The bleeding has ceased.

 


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  		Figure 5b. Embolization of a large facial AVM in a 4-year-old child with intractable oral hemorrhage. (a) Lateral angiogram of left external carotid artery shows mandibular (arrows) and maxillary (arrowheads) portions of facial AVM. (b) Unsubtracted lateral angiogram during embolization with 8% EVAC by means of direct puncture into the mandible with a 21-gauge needle. (c) Unsubtracted lateral angiogram after embolization, showing the cast of EVAC in the mandibular AVM (arrows). (d) Lateral angiogram of left external carotid artery after embolization shows good flow reduction in the AVM. The bleeding has ceased.

 


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  		Figure 5c. Embolization of a large facial AVM in a 4-year-old child with intractable oral hemorrhage. (a) Lateral angiogram of left external carotid artery shows mandibular (arrows) and maxillary (arrowheads) portions of facial AVM. (b) Unsubtracted lateral angiogram during embolization with 8% EVAC by means of direct puncture into the mandible with a 21-gauge needle. (c) Unsubtracted lateral angiogram after embolization, showing the cast of EVAC in the mandibular AVM (arrows). (d) Lateral angiogram of left external carotid artery after embolization shows good flow reduction in the AVM. The bleeding has ceased.

 


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  		Figure 5d. Embolization of a large facial AVM in a 4-year-old child with intractable oral hemorrhage. (a) Lateral angiogram of left external carotid artery shows mandibular (arrows) and maxillary (arrowheads) portions of facial AVM. (b) Unsubtracted lateral angiogram during embolization with 8% EVAC by means of direct puncture into the mandible with a 21-gauge needle. (c) Unsubtracted lateral angiogram after embolization, showing the cast of EVAC in the mandibular AVM (arrows). (d) Lateral angiogram of left external carotid artery after embolization shows good flow reduction in the AVM. The bleeding has ceased.

 
There were two transient postembolization complications. One patient with a right frontal paramedian meningioma (case 2) experienced a mild increase in a preexisting left-sided hemiparesis after embolization. A CT scan after the procedure did not show additional edema or intratumor hemorrhage. The following day the patient returned to baseline condition before the surgery. A second patient (case 6) experienced increased numbness in the distribution of the maxillary division of the trigeminal nerve after embolization of the artery of the foramen rotundum. The patient returned to baseline condition in 3 weeks.

In two patients with unresectable AVMs, symptoms from hemorrhage and mass effect improved. The patient with arteriovenous fistula was cured by embolization. Of the 15 patients who underwent surgery, 11 had total resection and four had subtotal resection. Estimated intraoperative blood loss and surgical resection type are listed in the Table.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Embolic agents are classified in three categories: mechanical devices, particles, and liquids. Depending on the hemodynamic and angioarchitectural factors, the optimal embolic agent can be chosen. Balloons are well adapted for test occlusions, permanent occlusion of large vessels such as carotid and vertebral arteries, and transarterial embolization of large direct arteriovenous fistulas (9,19,20). Pushable coils, delivered from a transarterial or transvenous approach, are useful for occlusion of arteriovenous fistulas (21). Guglielmi detachable coils (Target Therapeutics, Fremont, Calif), which can be positioned accurately and detached by means of electrolysis, are primarily used for embolization of intracranial aneurysms (22). They are also useful in the embolization of arteriovenous fistulas, to safely form the initial meshwork in which pushable coils (more thrombogenic and less expensive) will be placed. Particles such as polyvinyl alcohol particles or Gelfoam can be used for the embolization of hypervascular tumors and AVMs. They are easy to use and especially useful for preoperative embolization of tumors. However, particulate embolization has a tendency to recanalize (23,24). Additionally, if any arteriovenous shunt is larger than the particle diameter, the particles may travel through the lesion and embolize in the lungs (25). Liquid embolic agents include cyanoacrylates, dehydrated ethanol, Ethibloc, and sodium tetradecyl sulfate (26). Cyanoacrylates, such as N-butyl cyanoacrylate (cyanoacrylate), are not totally permanent (27), but are one of the longest lasting (11,28). However, cyanoacrylate is difficult to use. Cyanoacrylate polymerizes on contact with ionic solutions such as saline or blood. Cyanoacrylate polymerization time can be controlled by the addition of various concentrations of ethiodol. Delivery of cyanoacrylate demands extensive familiarity with the procedure and careful management of many factors, including control of polymerization time, velocity of injection, and handling of microcatheters. Inherent in the use of cyanoacrylate is the risk of gluing the microcatheter in place (29) with associated risk of severe complications, such as thrombosis or vessel rupture and hemorrhage. Furthermore, to avoid gluing the catheter, one must inject cyanoacrylate quickly and continuously, sacrificing precise control.

EVAC is a liquid embolic agent that, similar to cyanoacrylate, polymerizes when injected into the vasculature. The least concentrated EVAC solution is the least viscous and is expected to have the most distal penetration. In this study, there was a substantial difference in viscosity and penetration between EVAC at 6%–6.5% and 8%, but no real difference between the 6% and 6.5%. We used EVAC as the single embolic material in 13 cases, and with coils in three cases and with polyvinyl alcohol particles in two, achieving a mean of 79% percentage occlusion. EVAC has several advantages over cyanoacrylate. It comes radiopaque in established concentrations and viscosities. Also, because it is nonadhesive, there is no risk of gluing the catheter. Thus the injection of EVAC can be performed as slow as necessary for precise delivery; it may even be stopped to check the degree of embolization and later resumed. However, if DMSO or EVAC is injected quickly, vasospasm can be induced, which can hinder EVAC penetration or trap the catheter. In our experience with both EVAC and cyanoacrylate, EVAC had less tendency to fragment in high-flow lesions. In contrast to cyanoacrylate, EVAC advanced as a single column, thereby lowering the risk of involuntary venous migration. Thus, the rheologic characteristics of EVAC make embolization with this material safer and more controllable than with cyanoacrylate.

However, EVAC has several drawbacks. EVAC cannot be injected a long distance in a small-diameter or slow-flow vessel. When embolization of meningiomas was performed with the microcatheter placed in a dural artery more than 2 cm from the tumor, EVAC could not be injected into the tumor vascular bed and remained in the arterial feeder. In our experience with similar cases by using cyanoacrylate, the same poor result would have happened; however, small particles would have reached the tumor bed, providing a better result. In this series, satisfactory embolization (filling of the lesion vessels with EVAC) was performed in those cases where EVAC was delivered close to the tumor or AVM vasculature, as shown in Figures 3–5. In contrast, EVAC injection into a large arteriovenous fistula entails the risk of unwanted venous migration. For example, in the patient with vertebral arteriovenous fistula, we feared venous migration. To overcome this limitation, embolization was first performed with coils to slow the flow and provide a meshwork before EVAC embolization.

EVAC Embolization requires the use of special DMSO-compatible microcatheters. The microcatheter cannot be reused and has to be changed after each feeder embolization. In addition, embolization with DMSO and EVAC can be painful; therefore, general anesthesia is recommended to provide patient comfort and to prevent patient movement. In addition, EVAC is dissolved in DMSO, a solvent that is angiotoxic if not use appropriately. Chaloupka et al (30) demonstrated that DMSO injected intraarterially in ascending pharyngeal artery of swine at a high dosage or with high injection rate induces vasospasm, vessel wall necrosis, and even subarachnoid hemorrhage. In a later study (15), clinical, angiographic, and histopathologic criteria were used to examine the microvascular toxicity of DMSO in the swine rete mirabile model. With a low dose rate (5.6 µL/sec) and low total dose of DMSO injected (0.5 mL), only minor transient vasospasm was seen and no necrosis or abnormal histologic findings of the vasculature were noted. In a study by Murayama et al (31), selective intraarterial injection of DMSO (0.3 mL injected over 40 seconds) and of EVAC in the ascending pharyngeal artery of swine was safe, with no angionecrosis or intracranial hemorrhage. Our acute histopathologic results confirm that slow injections and low concentrations of DMSO did not induce angionecrosis or hemorrhage. In addition, we report for the first time, to our knowledge, long-term follow-up at 12 months after EVAC embolization of swine retia, which shows persistent angiographic occlusion of the embolized rete, without substantial histologic recanalization. In addition, no angionecrosis or extravasation of the embolic material was noticed. At 12 months, there was persistent chronic inflammation, less pronounced than at 3 or 6 months (31). The angiotoxicity of EVAC and DMSO delivered with slow injection appears less pronounced than the angiotoxicity reported in previous studies (32–34) of polyvinyl alcohol particles and cyanoacrylate, which demonstrated some angionecrosis and extravascular migration of the embolic material.

In our series, we observed two transient complications. One patient with a paramedian meningioma had a mild increase in a preexisting left-sided hemiparesis after EVAC embolization of the middle meningeal artery. CT scan and review of the angiogram did not show any cause for this deterioration and the patient recovered overnight. We believe that this complication was not related to the embolization procedure but can be explained by the temporary mild increase in preexisting deficits frequently observed after anesthesia. Alternatively, this may have been secondary to mild tumor swelling after the embolization. Another patient had a temporary increase in numbness of the right cheek, in the distribution of the second division of the trigeminal nerve, after wedge-flow embolization of the artery of the foramen rotundum. This complication may have been caused by direct ischemic injury or by DMSO toxicity. To our knowledge, there are no reports in the literature of the neurotoxic effects of EVAC or DMSO, and from our experience we think this complication could have happened after embolization by using cyanoacrylate or with small (50-µm) particles. This is because liquid embolic agents or small particles can penetrate the vasa nervorum beyond the point of effective anastomoses and therefore induce nerve ischemia. Although the nature of this deficit was transitory following this complication, we did not performed embolization of dural arteries the potentially supply cranial nerves, and we do not recommend the use of EVAC in this situation.

In conclusion, the experimental long-term study results showed that EVAC produced an effective and permanent occlusion of swine rete vessels, with no recanalization at 12-month follow-up. The pilot clinical study showed that EVAC was effective when it was delivered, either by selective microcatheterization or by direct percutaneous puncture, in proximity to the tumor vascular bed or arteriovenous shunts. However, embolization performed at a distance from the lesion resulted in proximal arterial occlusions. Compared with cyanoacrylate, EVAC is safer and more controllable. Further research on EVAC is warranted.


   FOOTNOTES
 
2 Current address: Department of Radiology, New York Hospital, 525 East 68th St, New York, NY. Back

9*. Vascular system, location unspecified Back

Y.P.G. is a paid advisor of Micro Therapeutics.

Abbreviations: AVM = arteriovenous malformation, DMSO = dimethyl sulfoxide, EVAC = ethylene vinyl alcohol copolymer

Author contributions: Guarantor of integrity of entire study, Y.P.G.; study concepts, Y.P.G., F.V.; study design, Y.P.G., Y.M.; literature research, Y.P.G., K.M., K.C., N.R.G.; clinical studies, Y.P.G., F.V., Y.M., G.R.D.; experimental studies, Y.M.; data acquisition, K.M., K.C., N.R.G.; data analysis, Y.P.G., K.M., K.C., N.R.G.; manuscript preparation, K.M., K.C., N.R.G.; definition of intellectual content, Y.P.G., F.V.; manuscript editing, Y.P.G., N.R.G., K.M., K.C.; manuscript review, F.V., G.R.D.; manuscript final version approval, Y.P.G., Y.M., N.R.G.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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