Clin Neuroradiol DOI 10.1007/s00062-015-0419-6
R e v i e w A rt i c l e
Evolution of Embolic Agents in Interventional Neuroradiology F. Brassel · D. Meila
Received: 6 April 2015 / Accepted: 3 June 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract The growth in understanding of the pathophysiological relationships between various neurovascular diseases in the past decades has increased the significance and need for endovascular treatment. Consequently, an extraordinary development of different embolic agents was indispensable. The present work first presents the historical milestones in the discovery of various embolic materials used for neurovascular interventions. In the second part, the current endovascular embolization procedures, requiring both liquid and solid embolic agents, are discussed. In some cases and diseases the combination of both may be mandatory. Special emphasis is placed on the consideration needed when choosing appropriate embolic materials, chiefly depending on the goal of the endovascular procedure. Furthermore, the present understanding of the specifics in angioarchitecture and hemodynamics, leading to the most suitable form of access to the vascular lesion, will be covered. Regarding the latter, it is important to note that the aim should always be to achieve optimal superselectivity while being aware of all approaches, ranging from transarterial and transvenous to direct puncture. Finally, based on the limitations of the currently available embolic D. Meila () · F. Brassel Department of Radiology and Neuroradiology, Klinikum Duisburg – Sana Kliniken, Zu den Rehwiesen 9, 47055 Duisburg, Germany e-mail: [email protected] e-mail: [email protected] F. Brassel e-mail: [email protected] D. Meila Department of Diagnostic and Interventional Neuroradiology, Medical School Hannover, Carl-Neuberg-Str.1, 30625 Hannover, Germany
materials, we present a brief outlook on the future of new liquid and solid embolic agents. Keywords Embolic agent · Embolization · NBCA · Onyx · Balloons · Coils History The use of embolic materials was significant for the development of what was to be later called, “Interventional Neuroradiology” (INR). Dawbarn was the first to report on embolization of head and neck cancers in 1904 [1]. The first embolization of a carotid-cavernous fistula (CCF) using a free piece of muscle through the internal carotid artery was attributed to Brooks in 1930 [2]. Nearly 30 years later, the first arteriovenous malformation (AVM) embolization was reported. Luessenhop and Spence performed this embolization with silastic beads in a surgically exposed common carotid artery in a case of a cerebral AVM [3]. Eight years later Doppmann et al. reported the first embolization of a spinal AVM with stainless-steel pellets [4]. For many years, the carotid artery direct puncture was the most common approach utilized until Djindjian et al. in France and Kricheff et al. in the USA demonstrated a novel approach using the transfemoral route for catheter embolization [5, 6]. The French and American schools, both leading INR at that time, highlighted the need for selectivity and superselectivity in endovascular procedures. One of the next major milestones in INR was documented by Serbinenko in Russia who was the first to use detachable balloons in the late 1960s. In 1971, he published his initial paper on the treatment of CCF with such balloons [7]. Debrun eventually introduced this new technique that allowed the inflation and release of a balloon in arteriovenous fis-
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tulae or in aneurysms to the Western world [8]. Detachable balloons soon disappeared from aneurysm treatment, yet they are still used for the embolization of single-hole fistulae of traumatic or congenital origin. The major advantage was and continues to be that balloons, made of either latex or silicone, can be removed and changed if the position or the size is inappropriate. Furthermore, they can be inflated to occlude vessels with a large diameter. Their main disadvantage formerly was that they deflated over time. Another purpose of using balloon catheter was the injection of acrylic glue in AVM without reflux. In this context Kerber, one of the key developers of neurointerventional procedures and material, developed a balloon catheter with a calibrated leak; allowing for distal fluid delivery while the balloon remained inflated and thus without reflux of acrylic glue [9]. In 1976, so-called “Gianturco coils” were introduced as embolic materials [10]. These stainless steel coils are small pieces of guidewire with the inner core removed. Initially, they had been utilized for permanent intravascular occlusion, like in the management of renal arteriovenous fistulas and in different tumors. As time went on, the use of coils in INR became more frequent in transvenous approaches, such as dural fistulas and CCF treatment [11]. Further, more flexible coils were developed, such that pushable coils, fiber coils and liquid coils for INR use were launched. The goal of using fibers in combination with the coils was to increase the thrombogenicity, while liquid coils are injectable supple embolics, still used to protect normal arteries, for example in the treatment of spinal vascular diseases. In 1991, Guglielmi et al. revolutionized the development of coils through being the first to use retrievable electrolytic detachable coils in the treatment of intracranial aneurysms [12]. Nowadays, most companies offer mechanical detachable coils that simplify the embolization procedure remarkably. Several years before Guglielmi, Hilal and Michelsen became the first to use low-viscosity silicone polymer as an intravascular adhesive for the embolization of vascular tumors [13]. As a result, a series of various embolic agents were introduced to the field of INR. Berenstein and Kricheff summarized the advantages and disadvantages of several embolic agents that were used in the late 1970s [14]. The agents at that time included Gelfoam, silicone spheres, polyvinyl alcohol foam (PVA), isobutyl-2-cyanoacrylate and silicone fluid mixtures. Interestingly, some of these materials, or their derivatives, continue to be employed today. Berenstein prominently reported the initial use of flow-controlled fluid embolization with silicone as an embolic agent [15]. He described the use of a modified double-lumen balloon catheter and silicone fluid-made radiopaque with tantalum powder. Flow control was achieved by manipulation of the balloon in a proximal artery, permitting the distribution of emboli to desired sites in distal arteries. However, silicone lost its significance over time, in particular because of the embracing of
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n-butyl-cyanoacrylate (NBCA). NBCA is the most important liquid embolic agent and has been used for decades, especially in the treatment of a number of vascular malformations. Besides the American and French schools, there was also a well-defined German school of INR. Lins and Wappenschmidt from Bonn detailed the value and application of selective external angiography in malignant facial tumors in the mid-1970s [16]. In 1978, Lins was actually the first person in Germany to obtain a PhD (Habilitation) in the field of INR, focused primarily on embolic agents. In 1981, he was joined by Solymosi, a well-recognized expert in the field, who worked closely and prolific with the first author of the present article in Bonn [17, 18]. In Tübingen, Voigt built one of the most important institutions in the early days of INR [19]. Among his co-workers that concentrated on INR, Schumacher became later Head of Department in Freiburg and Thron in Aachen. Bien, from Freiburg and also a specialist in INR, later became Head of Department in Marburg. Another important INR school needs to be mentioned which was founded by Zeumer, later Head of Department in Hamburg. Last but not the least, Kühne and colleagues formed one of the busiest high-load INR Departments in Essen and many of his senior physicians now hold leading appointments in Germany. Kühne was one of the first to ® use and recognize Ethibloc as an excellent liquid embolic agent for embolization of vascular tumors and AVMs in the head and neck [20]. As a point of interest, the first author of ® the present work also used Ethibloc with great success for many years in various vascular malformations [21]. Unfortunately, this product is no longer in the market. Current Endovascular Embolization Procedures As described earlier, current endovascular embolization procedures utilize either liquid embolic agents or solid materials. As also mentioned, there are specific cases and diseases where the combination of both is often necessary, and so choosing the appropriate embolic agent is generally based on the goal of the endovascular procedure and the approach. Furthermore, we believe one should be very familiar with a relatively small group of embolic materials. Approaches Depending on the specific angioarchitecture (Fig. 1) and on the localization of the vascular lesion, a sole transarterial or transvenous approach, or even the combination of both, is required. In AVM, the aim should be the closure of the whole nidus, ideally both the in- and outflow-zone, and without occluding normal surrounding vessels. The endovascular procedure of choice is primarily a transarterial superselective microcatheter-based approach followed by emboliza-
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Fig. 1 Hemodynamic classification of arteriovenous malformation (AVM), modified from [21]. a and b Arteriovenous fistulas with one fistula between one (a) or multiple (b) artery/arteries and vein/veins. c Arteriovenous malformation (AV-angioma) with multiple communi-
cating shunting vessels (nidus). d Vascular malformation (as in dural AV-fistula) with one or more feeding arteries and a collateral vascular network, shunting directly—fistulous-type—into one draining vein
tion using liquid embolic agents with different viscosities to achieve a casting of the whole nidus [22]. Reflux, however, can sometimes be difficult to control and may jeopardize a complete embolization, as declared by Chapot et al. [23]. They developed the so-called “pressure cooker” technique, designed to create an anti-reflux plug by trapping the detachable part of an Onyx-compatible microcatheter with coils and glue to obtain wedge-flow conditions. Doing so, the authors reported a better understanding of macrofistulous AVMs as well as a more comprehensive, forceful and controlled ® Onyx embolization. Another technique to prevent liquid embolic agent reflux is the use of an additional balloon. Utilizing a double-lumen balloon catheter in this context has already been a well-established practice for many years [15]. A sole transarterial approach fails when the feeding arteries are not reachable by microcatheter. Embolization in these cases would lead to proximal occlusion of the feeding arteries, and so a microcatheter-based transvenous approach may help. When most of the arterial feeders reach one fistula point where venous drainage begins, a transvenous approach in wedging position with a subsequent retrograde embolization might be favored. Transvenous retrograde intranidal microcatheter embolization also allows a complete AVM nidus ® casting with liquid embolic material-like Onyx (Fig. 2). However, a combined transarterial and transvenous method using a “kissing microcatheter technique” can be chosen in very special and difficult cases (Fig. 2). This technique has
recently been proven to show positive results, especially in the treatment of pediatric Vein of Galen malformations [24]. The application of embolic and sclerosing agents by percutaneous direct puncture is predominantly indicated for the treatment of low-flow vascular malformations, like venous or lymphatic malformations. However, in difficult cases of tiny and plexiform AVM with very small and tortuous vessels, a superselective endovascular approach by microcatheter is not always feasible. When neither the transarterial nor the transvenous approach in extracranial neurovascular diseases succeeds, one may think about percutaneous direct puncture with very small cannulas. Before injecting liquid embolic agents, the correct position of the tip of the needle must be controlled by an angiographic run. With this, it must be ensured that the tip of the needle is located intranidal and not in the adjacent tissue before deployment of a liquid embolic agent. Indication and Safety Aspects of Embolization Procedures As the general basis of safety aspects in any embolization procedures, mastering functional vascular anatomy is crucial. Nonetheless, specific technical complications in the interventional treatment may occur. This might be in the form of vessel perforation, undesired embolization of normal vessels, and passage of embolic materials away from the target. Therefore, the highest selectivity and accuracy is mandatory when treating any vascular malformation. Usu-
Fig. 2 Retrograde transvenous embolization with Onyx® using the “kissing microcatheter technique” in a Vein of Galen malformation. a Lateral unsubtracted view showing coils and Onyx® casts. b Digital subtraction angiography (DSA) shows a transvenous intranidal microcatheter contrast injection with early filling of the venous outflow. c Roadmap of the same projection showing the initial Onyx® cast at the beginning of the embolization
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ally, anastomoses are not visualized on serial global angiographies, but they do nevertheless always exist. They may open under the following circumstances as Geibprasert et al. [25] have summarized: (1) with increased intra-arterial pressure, for example, during superselective injections, (2) in the presence of high-flow shunts as a consequence of the “sump effect”, or (3) as collateral routes when occlusions of the major intracranial arteries take place. Concerning the indication and need for treatment, a meticulous consideration of the risk between endovascular treatment and natural history is indispensable. The therapeutic goal must always be defined by clinical outcome and not just by angiographic pictures. The main purpose is never just the occlusion of a vessel or the reduction of flow, but rather the reduction of the neurovascular disease-related risks and symptoms. Therefore, the indication for treatment always has to be made interdisciplinarily, taking into account any therapeutic alternatives. Widely Used Embolic Agents Currently, it is mainly two different groups of embolic materials that are used in INR, being liquid and solid agents. Liquid embolic materials include adhesive agents, like ® acrylates (e.g., n-butyl cyanoacrylate, NBCA, Histoacryl ), non-adhesive agents, such as ethylene-vinyl alcohol copoly® mer (EVOH, ONYX ), and cytotoxics, like Ethanol (98 %) ® and Polydocanol (Aethoxysklerol ). Solid embolic materials are used, for example, in the form of small particles, ® such as PVA, Embospheres , metal spirals (coils) of platinum, tungsten or stainless steel, and detachable balloons, all of which lead to a mechanical obliteration of the vessel associated with flow deceleration and subsequent thrombosis. Both liquid and solid embolic materials do have specific applications, though. Generally speaking, liquid embolic materials may permit a vascular area to be homogeneously filled. This means that a secondary reopening of the embolized area will barely take place. This is the reason why liquid embolics are excellently suited for the treatment of complex plexiform AVM. Compared to the use of particulate embolics, they offer the advantage of recanalization risk and frequency being significantly reduced. However, too fast an injection of liquid embolic materials may result in retrograde embolization in the worst case in normal vessels, potentially leading to an entrapped microcatheter tip in one of the vessels itself. This risk is more often seen when using acrylates. In contrast, a passage of the embolic agent into the draining venous outflow without complete occlusion of the nidus may compromise physiologic venous drainage with possible complications like venous congestion that harbors even more risk through venous infarction and bleeding. Passage of embolic material to the heart or lungs is another feared adverse effect when dealing with uncontrollable liq-
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F. Brassel, D. Meila ®
®
uid materials. Acrylates like Histoacryl and Glubran 2 ® polymerize in contact with blood while Ethibloc , a protein derived from maize and dissolved in alcohol, precipitates. ® Depending on the precise pathophysiology, Ethibloc has been diluted with Lipiodol and, in particular, with Lipiodol ® and additional alcohol [21]. Nowadays, the use of Onyx is widely accepted in neuroradiologic interventions, and is becoming more and more important for other types of interventions, as well. In the following we present the most common and in our opinion the most important embolic agents. It would be impossible and out of the scope of this article to mention the full gamut of such materials which have been utilized to date. N-Butyl Cyanoacrylate Up until a few years ago, NBCA was the most frequently employed liquid embolic agent. It is also known as “Glue” and was developed to replace isobutyl cyanoacrylate, presumed to be carcinogenic. NBCA polymerizes almost immediately upon contact with ionic fluid, consequently resulting in a high risk of microcatheter entrapment within the artery. Polymerization that happens too early within the therapeutic microcatheter is prevented by rinsing it with a nonionic solution, such as a dextrose solution. NBCA can be mixed with ethiodized oil (Lipiodol or Ethiodol) to control the rate of polymerization and with tantalum or tungsten powder to increase radiopacity. Although NBCA is considered a permanent embolic agent that initiates a significant vascular inflammatory reaction, recanalization may occur. The possibility of recanalization is especially high when NBCA is deposited too proximally to the arterial feeder without casting of the whole AVM nidus. Ethylene-Vinyl Alcohol Copolymer ®
Onyx is a more recently developed liquid embolic agent that is used for the embolization of vascular malformations. It is comprised of ethylene-vinyl alcohol copolymer, available in various concentrations, dissolved in dimethyl sulfoxide (DMSO) and suspended in micronized tantalum powder ® to provide contrast for fluoroscopy. Onyx is thought to be a more manageable agent than NBCA as it solidifies slowly from outside to inside while the DMSO solvent diffuses, reducing the risk of microcatheter entrapment. Prolonged ® and repeated Onyx injections within the same AVM pedicle are possible and allow it to be pushed more distally ® toward and within the nidus. Like NBCA, Onyx is also considered a permanent embolic agent although recanalization is possible, as well.
Evolution of Embolic Agents in Interventional Neuroradiology
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Coils
Future Outlook
Pushable coils have long been used in the endovascular treatment of arterial bleeding in a variety of vascular territories. The disadvantage to the first generation of these coils had been that once they were deployed, retrieving them was no longer possible. The next generation of coils was the electrolytic detachable coils by Guglielmi (GDC). Now, there is a vast range of coils that can also be detached mechanically, and the fact that coils can be repositioned, retrieved or changed is a great advantage, especially if the coil is not at the desired position or not of the optimal size. In addition to the originally bare coils, hydro coils, liquid coils, fiber coils, and bioactive coils are all different types of coils currently available. Moreover, unique sizes, flexibilities, shapes, and forms are available, from very large coils, volume coils to very small, soft coils. Coils are mostly used for the endovascular treatment of intracranial arterial aneurysms, not typically used to occlude AVM feeders. However, they may be useful for slowing flow within a particular compartment of certain AVF and thus, to facilitate subsequent use of a liquid embolic agent. Detachable coils are also used for vessel occlusion, like in deconstructive therapy, and the transvenous approach to dural AVF and VGM.
Concerning solid agents, one must certainly mention the novel and very promising device, the Woven Endobridge ® (WEB II ) for intracranial aneurysm treatment. The WEB ® II is a self-expanding, nitinol, mesh device designed to achieve aneurysm occlusion after endosaccular deployment. Preliminary results from the WEBCAST trials have been very promising [26]; nonetheless, long-term results, especially concerning aneurysmal regrowth, are still lacking. Parent artery sacrifice is a valuable tool in the treatment of select vascular lesions. With detachable balloons no longer being available in many countries, most sacrifices are performed with primary coil embolization. However, traditional coil embolization as the primary means of parent artery sacrifice can be expensive, with high radiation expo® sure. A new hybrid coil, the Penumbra occlusion device (POD), was designed specifically to achieve occlusion in relatively large arteries, such as the carotid or vertebral artery [27]. The conclusions of a feasibility study in a swine ® model was that a carotid artery sacrifice using a novel POD ® device was safe and effective. Furthermore, the POD significantly reduced radiation and material costs compared with the other described endovascular techniques. Another ® new occlusion device on the market is the MVP (micro vascular plug system). It was designed to occlude vessels quickly with a single re-sheathable device. With regards to coil technology in the context of these new tools, one may wonder what future investigations will show. Especially in the nanotechnology era, perhaps further improvement of coils, making them more suitable, softer and smaller, will ® take place. New liquid embolic agents, like PHIL (precipitating hydrophobic injectable liquid), seem to be promising. ® As the suspended micronized tantalum powder in Onyx is ® responsible for its dark color, PHIL may be a truly viable alternative option as no tantalum powder is used for radiopacity. Thus, it may be favored for the treatment of visible superficial head and neck vascular malformations. The preliminary results from studies with another new liquid ® embolic agent called Squid demonstrated that the agent behaved safely and effectively in treatment of cerebral AVMs, AV fistulas, tumors, and aneurysms with satisfactory ® ® obliteration rates [28]. However, both PHIL and Squid are liquid embolics on the basis of ethylene-vinyl alcohol ® copolymer like Onyx . Ultimately, as rapidly as INR is growing, further research and development of more sophisticated devices and embolic agents is warranted and obligatory for continued progress in the field (Fig. 3).
Particles Particles like PVA are mostly used for the preoperative embolization of highly vascularized tumors to diminish the perioperative bleeding risk and induce tumor necrosis. They are available in 50–1000 μm sizes. Based on their composition and size, particles do not reach and bridge the fistulous connections in AVM with their inflow zone, nidus, and outflow zone. They may, though, occlude arterial feeders at the inflow zone. With the expected vessel recanalization after PVA embolization, they are no more eligible for treatment of AVM. However, they continue to have a strong relevance for the endovascular treatment of epistaxis. Ethanol Ethyl alcohol (98 % ethanol) and polydocanol are sclerosing agents that produce no immediate mechanical embolization but a severe inflammatory reaction because of cytotoxicity. Strong alcohol injections play an important role in the treatment of venous and lymphatic malformations by direct puncture, also known as sclerotherapy. There is little relevance for the use of ethanol in AVM due to its extremely high complication rates.
Acknowledgment The authors would like to thank Jacqueline Dornbusch for carefully reading the manuscript.
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Fig. 3 a Shows Ethibloc®, a protein derived from maize and dissolved in alcohol, that precipitated, while acrylates polymerizes in contact with blood. Note its yellowish-white colour. Depending on the particular pathophysiology, Ethibloc® has been diluted with Lipiodol or with Lipiodol and additional alcohol [21]. b Shows Onyx®, a liquid embolic
material consisting of ethylene-vinyl alcohol copolymer, available in various concentrations dissolved in dimethyl sulfoxide (DMSO) and suspended micronized tantalum powder to provide contrast for fluoroscopy. The tantalum is responsible for its dark colour
Financial Disclosure The authors have no financial relationships relevant to this article to disclose.
10. Wallace S, Gianturco C, Anderson JH, Goldstein HM, Davis LJ, Bree RL. Therapeutic vascular occlusion utilizing steel coil technique: clinical applications. AJR Am J Roentgenol. 1976;127(3):381–7. 11. Halbach VV, Higashida RT, Hieshima GB, Hardin CW, Pribram H. Transvenous embolization of dural fistulas involving the cavernous sinus. AJNR Am J Neuroradiol. 1989;10(2):377–83. 12. Guglielmi G, Viñuela F, Sepetka I, Macellari V. Electrothrombosis of saccular aneurysms via endovascular approach. Part 1: electrochemical basis, technique, and experimental results. J Neurosurg. 1991;75(1):1–7. 13. Hilal SK, Michelsen JW. Therapeutic percutaneous embolization for extra-axial vascular lesions of the head, neck, and spine. J Neurosurg. 1975;43(3):275–87. 14. Berenstein A, Kricheff II. Catheter and material selection for transarterial embolization: technical considerations. II. Materials. Radiology. 1979;132(3):631–9. 15. Berenstein A. Flow-controlled silicone fluid embolization. AJR Am J Roentgenol. 1980;134(6):1213–8. 16. Lins E, Wappenschmidt J. Zur Informationsbreite und therapeutischen Anwendung der selektiven Carotis externa-Angiographie bei malignen Prozessen des Gesichtsschädels. Laryngol Rhinol Otol (Stuttg.). 1976;55:62–65. 17. Brassel F, Solymosi L. An unusual congenital arteriovenous fistula of the vertebral artery and its embolization by a detachable balloon catheter. Neurosurg Rev. 1988;11(1):99–101. 18. Brassel F, Dettmers C, Nierhaus A, Hartmann A, Solymosi L. An intravascular technique to occlude the middle cerebral artery in baboons. Neuroradiology. 1989;31(5):418–24. 19. Voigt K, Djindjian R. [Diagnostic and therapeutic results of superselective cerebral angiographies in pathologic lesions in the vascular area of the human external carotid artery (author’s transl)]. Radiologe. 1976;16(10):436–43. 20. Kühne D, Helmke K. Embolization with “Ethibloc” of vascular tumors and arteriovenous malformations in the head and neck. Neuroradiology. 1982;23(5):253–8. 21. Brassel F. Entwicklung und Erprobung eines Gefäßmodells zur Simulation einer Embolisation mit Ethibloc® bei spinaler duraler arteriovenöser Malformation. Bremen: H.M. Hauschild GmbH; 1997.
Funding Source No external funding was secured for this study. Conflict of Interest On behalf of both authors, the corresponding author states that there is no conflict of interest.
References 1. Dawbarn RHM. The starvation operation for malignancy in the external carotid area. J Am Med Assoc. 1904;13:792–5. 2. Brooks B. The treatment of traumatic arteriovenous fistula. South Med J. 1930;23:100–6. 3. Luessenhop AJ, Spence WT. Artificial embolization of cerebral arteries. Report of use in a case of arteriovenous malformation. J Am Med Assoc. 1960;172:1153–5. 4. Doppman JL, Chiro GD, Ommaya A. Obliteration of spinal-cord arteriovenous malformation by percutaneous embolisation. Lancet. 1968;1(7540):477. 5. Djindjian R, Houdart R, Cophignon J, Hurth M, Comoy J. 1st trials of embolization by the femoral route with muscle fragments in a case of medullary angioma and a case of angioma supplied by the external carotid. Rev Neurol (Paris). 1971;125(2):119–30. 6. Kricheff II, Madayag M, Braunstein P. Transfemoral catheter embolization of cerebral and posterior fossa arteriovenous malformations. Radiology. 1972;103(1):107–11. 7. Serbinenko FA. [Occlusion of the cavernous portion of the carotid artery with a balloon as a method of treating carotid-cavernous anastomosis]. Vopr Neirokhir. 1971;35(6):3–9. (Russian. No abstract available). 8. Debrun G, Lacour P, Caron JP, Hurth M, Comoy J, Keravel Y. Inflatable and released balloon technique experimentation in dog— application in man. Neuroradiology. 1975;9(5):267–71. 9. Kerber C. Balloon catheter with a calibrated leak. A new system for superselective angiography and occlusive catheter therapy. Radiology. 1976;120(3):547–50.
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Evolution of Embolic Agents in Interventional Neuroradiology 22. Brassel F, Meila D, Papke K. Vascular interventions in the head and neck region. Part 2: procedures for vessel occlusion. Radiologe. 2011;51(6):519–33. 23. Chapot R, Stracke P, Velasco A, Nordmeyer H, Heddier M, Stauder M, Schooss P, Mosimann PJ. The pressure cooker technique for the treatment of brain AVMs. J Neuroradiol. 2014;41(1):87–91. 24. Meila D, Hannak R, Feldkamp A, Schlunz-Hendann M, Mangold A, Jacobs C, Papke K, Brassel F. Vein of Galen aneurysmal malformation: combined transvenous and transarterial method using a “kissing microcatheter technique”. Neuroradiology. 2012;54(1):51–9. 25. Geibprasert S, Pongpech S, Armstrong D, Krings T. Dangerous extracranial-intracranial anastomoses and supply to the cranial nerves: vessels the neurointerventionalist needs to know. AJNR Am J Neuroradiol. 2009;30(8):1459–68.
7 26. Pierot L, Spelle L, Costalat V, Szikora I, Klisch J, Herbreteau D, Holtmannspoetter M, Weber W, Liebig T, Cognard C, Bonafé A, Moret J, Byrne J, Molyneux A. WEB Flow Disruption: Preliminary Results from WEBCAST trial. J Neurointerv Surg. 2014;6(Suppl 1):A51. doi:10.1136/neurintsurg-2014-011343.96. 27. Spiotta AM, Turner RD, Chaudry MI, Turk AS, Hui FK, Schonholz C. Carotid sacrifice with a single Penumbra occlusion device: a feasibility study in a swine model. J Neurointerv Surg. 2014. pii: neurintsurg-2014-011461. doi:10.1136/neurintsurg-2014-011461. 28. Akmangit I, Daglioglu E, Kaya T, Alagoz F, Sahinoglu M, Peker A, Derakshani S, Dede D, Belen D, Arat A. Preliminary experience with squid: a new liquid embolizing agent for AVM, AV fistulas and tumors. Turk Neurosurg. 2014;24(4):565–70.
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R e v i e w A rt i c l e
Evolution of Embolic Agents in Interventional Neuroradiology F. Brassel · D. Meila
Received: 6 April 2015 / Accepted: 3 June 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract The growth in understanding of the pathophysiological relationships between various neurovascular diseases in the past decades has increased the significance and need for endovascular treatment. Consequently, an extraordinary development of different embolic agents was indispensable. The present work first presents the historical milestones in the discovery of various embolic materials used for neurovascular interventions. In the second part, the current endovascular embolization procedures, requiring both liquid and solid embolic agents, are discussed. In some cases and diseases the combination of both may be mandatory. Special emphasis is placed on the consideration needed when choosing appropriate embolic materials, chiefly depending on the goal of the endovascular procedure. Furthermore, the present understanding of the specifics in angioarchitecture and hemodynamics, leading to the most suitable form of access to the vascular lesion, will be covered. Regarding the latter, it is important to note that the aim should always be to achieve optimal superselectivity while being aware of all approaches, ranging from transarterial and transvenous to direct puncture. Finally, based on the limitations of the currently available embolic D. Meila () · F. Brassel Department of Radiology and Neuroradiology, Klinikum Duisburg – Sana Kliniken, Zu den Rehwiesen 9, 47055 Duisburg, Germany e-mail: [email protected] e-mail: [email protected] F. Brassel e-mail: [email protected] D. Meila Department of Diagnostic and Interventional Neuroradiology, Medical School Hannover, Carl-Neuberg-Str.1, 30625 Hannover, Germany
materials, we present a brief outlook on the future of new liquid and solid embolic agents. Keywords Embolic agent · Embolization · NBCA · Onyx · Balloons · Coils History The use of embolic materials was significant for the development of what was to be later called, “Interventional Neuroradiology” (INR). Dawbarn was the first to report on embolization of head and neck cancers in 1904 [1]. The first embolization of a carotid-cavernous fistula (CCF) using a free piece of muscle through the internal carotid artery was attributed to Brooks in 1930 [2]. Nearly 30 years later, the first arteriovenous malformation (AVM) embolization was reported. Luessenhop and Spence performed this embolization with silastic beads in a surgically exposed common carotid artery in a case of a cerebral AVM [3]. Eight years later Doppmann et al. reported the first embolization of a spinal AVM with stainless-steel pellets [4]. For many years, the carotid artery direct puncture was the most common approach utilized until Djindjian et al. in France and Kricheff et al. in the USA demonstrated a novel approach using the transfemoral route for catheter embolization [5, 6]. The French and American schools, both leading INR at that time, highlighted the need for selectivity and superselectivity in endovascular procedures. One of the next major milestones in INR was documented by Serbinenko in Russia who was the first to use detachable balloons in the late 1960s. In 1971, he published his initial paper on the treatment of CCF with such balloons [7]. Debrun eventually introduced this new technique that allowed the inflation and release of a balloon in arteriovenous fis-
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tulae or in aneurysms to the Western world [8]. Detachable balloons soon disappeared from aneurysm treatment, yet they are still used for the embolization of single-hole fistulae of traumatic or congenital origin. The major advantage was and continues to be that balloons, made of either latex or silicone, can be removed and changed if the position or the size is inappropriate. Furthermore, they can be inflated to occlude vessels with a large diameter. Their main disadvantage formerly was that they deflated over time. Another purpose of using balloon catheter was the injection of acrylic glue in AVM without reflux. In this context Kerber, one of the key developers of neurointerventional procedures and material, developed a balloon catheter with a calibrated leak; allowing for distal fluid delivery while the balloon remained inflated and thus without reflux of acrylic glue [9]. In 1976, so-called “Gianturco coils” were introduced as embolic materials [10]. These stainless steel coils are small pieces of guidewire with the inner core removed. Initially, they had been utilized for permanent intravascular occlusion, like in the management of renal arteriovenous fistulas and in different tumors. As time went on, the use of coils in INR became more frequent in transvenous approaches, such as dural fistulas and CCF treatment [11]. Further, more flexible coils were developed, such that pushable coils, fiber coils and liquid coils for INR use were launched. The goal of using fibers in combination with the coils was to increase the thrombogenicity, while liquid coils are injectable supple embolics, still used to protect normal arteries, for example in the treatment of spinal vascular diseases. In 1991, Guglielmi et al. revolutionized the development of coils through being the first to use retrievable electrolytic detachable coils in the treatment of intracranial aneurysms [12]. Nowadays, most companies offer mechanical detachable coils that simplify the embolization procedure remarkably. Several years before Guglielmi, Hilal and Michelsen became the first to use low-viscosity silicone polymer as an intravascular adhesive for the embolization of vascular tumors [13]. As a result, a series of various embolic agents were introduced to the field of INR. Berenstein and Kricheff summarized the advantages and disadvantages of several embolic agents that were used in the late 1970s [14]. The agents at that time included Gelfoam, silicone spheres, polyvinyl alcohol foam (PVA), isobutyl-2-cyanoacrylate and silicone fluid mixtures. Interestingly, some of these materials, or their derivatives, continue to be employed today. Berenstein prominently reported the initial use of flow-controlled fluid embolization with silicone as an embolic agent [15]. He described the use of a modified double-lumen balloon catheter and silicone fluid-made radiopaque with tantalum powder. Flow control was achieved by manipulation of the balloon in a proximal artery, permitting the distribution of emboli to desired sites in distal arteries. However, silicone lost its significance over time, in particular because of the embracing of
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n-butyl-cyanoacrylate (NBCA). NBCA is the most important liquid embolic agent and has been used for decades, especially in the treatment of a number of vascular malformations. Besides the American and French schools, there was also a well-defined German school of INR. Lins and Wappenschmidt from Bonn detailed the value and application of selective external angiography in malignant facial tumors in the mid-1970s [16]. In 1978, Lins was actually the first person in Germany to obtain a PhD (Habilitation) in the field of INR, focused primarily on embolic agents. In 1981, he was joined by Solymosi, a well-recognized expert in the field, who worked closely and prolific with the first author of the present article in Bonn [17, 18]. In Tübingen, Voigt built one of the most important institutions in the early days of INR [19]. Among his co-workers that concentrated on INR, Schumacher became later Head of Department in Freiburg and Thron in Aachen. Bien, from Freiburg and also a specialist in INR, later became Head of Department in Marburg. Another important INR school needs to be mentioned which was founded by Zeumer, later Head of Department in Hamburg. Last but not the least, Kühne and colleagues formed one of the busiest high-load INR Departments in Essen and many of his senior physicians now hold leading appointments in Germany. Kühne was one of the first to ® use and recognize Ethibloc as an excellent liquid embolic agent for embolization of vascular tumors and AVMs in the head and neck [20]. As a point of interest, the first author of ® the present work also used Ethibloc with great success for many years in various vascular malformations [21]. Unfortunately, this product is no longer in the market. Current Endovascular Embolization Procedures As described earlier, current endovascular embolization procedures utilize either liquid embolic agents or solid materials. As also mentioned, there are specific cases and diseases where the combination of both is often necessary, and so choosing the appropriate embolic agent is generally based on the goal of the endovascular procedure and the approach. Furthermore, we believe one should be very familiar with a relatively small group of embolic materials. Approaches Depending on the specific angioarchitecture (Fig. 1) and on the localization of the vascular lesion, a sole transarterial or transvenous approach, or even the combination of both, is required. In AVM, the aim should be the closure of the whole nidus, ideally both the in- and outflow-zone, and without occluding normal surrounding vessels. The endovascular procedure of choice is primarily a transarterial superselective microcatheter-based approach followed by emboliza-
Evolution of Embolic Agents in Interventional Neuroradiology
3
Fig. 1 Hemodynamic classification of arteriovenous malformation (AVM), modified from [21]. a and b Arteriovenous fistulas with one fistula between one (a) or multiple (b) artery/arteries and vein/veins. c Arteriovenous malformation (AV-angioma) with multiple communi-
cating shunting vessels (nidus). d Vascular malformation (as in dural AV-fistula) with one or more feeding arteries and a collateral vascular network, shunting directly—fistulous-type—into one draining vein
tion using liquid embolic agents with different viscosities to achieve a casting of the whole nidus [22]. Reflux, however, can sometimes be difficult to control and may jeopardize a complete embolization, as declared by Chapot et al. [23]. They developed the so-called “pressure cooker” technique, designed to create an anti-reflux plug by trapping the detachable part of an Onyx-compatible microcatheter with coils and glue to obtain wedge-flow conditions. Doing so, the authors reported a better understanding of macrofistulous AVMs as well as a more comprehensive, forceful and controlled ® Onyx embolization. Another technique to prevent liquid embolic agent reflux is the use of an additional balloon. Utilizing a double-lumen balloon catheter in this context has already been a well-established practice for many years [15]. A sole transarterial approach fails when the feeding arteries are not reachable by microcatheter. Embolization in these cases would lead to proximal occlusion of the feeding arteries, and so a microcatheter-based transvenous approach may help. When most of the arterial feeders reach one fistula point where venous drainage begins, a transvenous approach in wedging position with a subsequent retrograde embolization might be favored. Transvenous retrograde intranidal microcatheter embolization also allows a complete AVM nidus ® casting with liquid embolic material-like Onyx (Fig. 2). However, a combined transarterial and transvenous method using a “kissing microcatheter technique” can be chosen in very special and difficult cases (Fig. 2). This technique has
recently been proven to show positive results, especially in the treatment of pediatric Vein of Galen malformations [24]. The application of embolic and sclerosing agents by percutaneous direct puncture is predominantly indicated for the treatment of low-flow vascular malformations, like venous or lymphatic malformations. However, in difficult cases of tiny and plexiform AVM with very small and tortuous vessels, a superselective endovascular approach by microcatheter is not always feasible. When neither the transarterial nor the transvenous approach in extracranial neurovascular diseases succeeds, one may think about percutaneous direct puncture with very small cannulas. Before injecting liquid embolic agents, the correct position of the tip of the needle must be controlled by an angiographic run. With this, it must be ensured that the tip of the needle is located intranidal and not in the adjacent tissue before deployment of a liquid embolic agent. Indication and Safety Aspects of Embolization Procedures As the general basis of safety aspects in any embolization procedures, mastering functional vascular anatomy is crucial. Nonetheless, specific technical complications in the interventional treatment may occur. This might be in the form of vessel perforation, undesired embolization of normal vessels, and passage of embolic materials away from the target. Therefore, the highest selectivity and accuracy is mandatory when treating any vascular malformation. Usu-
Fig. 2 Retrograde transvenous embolization with Onyx® using the “kissing microcatheter technique” in a Vein of Galen malformation. a Lateral unsubtracted view showing coils and Onyx® casts. b Digital subtraction angiography (DSA) shows a transvenous intranidal microcatheter contrast injection with early filling of the venous outflow. c Roadmap of the same projection showing the initial Onyx® cast at the beginning of the embolization
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ally, anastomoses are not visualized on serial global angiographies, but they do nevertheless always exist. They may open under the following circumstances as Geibprasert et al. [25] have summarized: (1) with increased intra-arterial pressure, for example, during superselective injections, (2) in the presence of high-flow shunts as a consequence of the “sump effect”, or (3) as collateral routes when occlusions of the major intracranial arteries take place. Concerning the indication and need for treatment, a meticulous consideration of the risk between endovascular treatment and natural history is indispensable. The therapeutic goal must always be defined by clinical outcome and not just by angiographic pictures. The main purpose is never just the occlusion of a vessel or the reduction of flow, but rather the reduction of the neurovascular disease-related risks and symptoms. Therefore, the indication for treatment always has to be made interdisciplinarily, taking into account any therapeutic alternatives. Widely Used Embolic Agents Currently, it is mainly two different groups of embolic materials that are used in INR, being liquid and solid agents. Liquid embolic materials include adhesive agents, like ® acrylates (e.g., n-butyl cyanoacrylate, NBCA, Histoacryl ), non-adhesive agents, such as ethylene-vinyl alcohol copoly® mer (EVOH, ONYX ), and cytotoxics, like Ethanol (98 %) ® and Polydocanol (Aethoxysklerol ). Solid embolic materials are used, for example, in the form of small particles, ® such as PVA, Embospheres , metal spirals (coils) of platinum, tungsten or stainless steel, and detachable balloons, all of which lead to a mechanical obliteration of the vessel associated with flow deceleration and subsequent thrombosis. Both liquid and solid embolic materials do have specific applications, though. Generally speaking, liquid embolic materials may permit a vascular area to be homogeneously filled. This means that a secondary reopening of the embolized area will barely take place. This is the reason why liquid embolics are excellently suited for the treatment of complex plexiform AVM. Compared to the use of particulate embolics, they offer the advantage of recanalization risk and frequency being significantly reduced. However, too fast an injection of liquid embolic materials may result in retrograde embolization in the worst case in normal vessels, potentially leading to an entrapped microcatheter tip in one of the vessels itself. This risk is more often seen when using acrylates. In contrast, a passage of the embolic agent into the draining venous outflow without complete occlusion of the nidus may compromise physiologic venous drainage with possible complications like venous congestion that harbors even more risk through venous infarction and bleeding. Passage of embolic material to the heart or lungs is another feared adverse effect when dealing with uncontrollable liq-
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F. Brassel, D. Meila ®
®
uid materials. Acrylates like Histoacryl and Glubran 2 ® polymerize in contact with blood while Ethibloc , a protein derived from maize and dissolved in alcohol, precipitates. ® Depending on the precise pathophysiology, Ethibloc has been diluted with Lipiodol and, in particular, with Lipiodol ® and additional alcohol [21]. Nowadays, the use of Onyx is widely accepted in neuroradiologic interventions, and is becoming more and more important for other types of interventions, as well. In the following we present the most common and in our opinion the most important embolic agents. It would be impossible and out of the scope of this article to mention the full gamut of such materials which have been utilized to date. N-Butyl Cyanoacrylate Up until a few years ago, NBCA was the most frequently employed liquid embolic agent. It is also known as “Glue” and was developed to replace isobutyl cyanoacrylate, presumed to be carcinogenic. NBCA polymerizes almost immediately upon contact with ionic fluid, consequently resulting in a high risk of microcatheter entrapment within the artery. Polymerization that happens too early within the therapeutic microcatheter is prevented by rinsing it with a nonionic solution, such as a dextrose solution. NBCA can be mixed with ethiodized oil (Lipiodol or Ethiodol) to control the rate of polymerization and with tantalum or tungsten powder to increase radiopacity. Although NBCA is considered a permanent embolic agent that initiates a significant vascular inflammatory reaction, recanalization may occur. The possibility of recanalization is especially high when NBCA is deposited too proximally to the arterial feeder without casting of the whole AVM nidus. Ethylene-Vinyl Alcohol Copolymer ®
Onyx is a more recently developed liquid embolic agent that is used for the embolization of vascular malformations. It is comprised of ethylene-vinyl alcohol copolymer, available in various concentrations, dissolved in dimethyl sulfoxide (DMSO) and suspended in micronized tantalum powder ® to provide contrast for fluoroscopy. Onyx is thought to be a more manageable agent than NBCA as it solidifies slowly from outside to inside while the DMSO solvent diffuses, reducing the risk of microcatheter entrapment. Prolonged ® and repeated Onyx injections within the same AVM pedicle are possible and allow it to be pushed more distally ® toward and within the nidus. Like NBCA, Onyx is also considered a permanent embolic agent although recanalization is possible, as well.
Evolution of Embolic Agents in Interventional Neuroradiology
5
Coils
Future Outlook
Pushable coils have long been used in the endovascular treatment of arterial bleeding in a variety of vascular territories. The disadvantage to the first generation of these coils had been that once they were deployed, retrieving them was no longer possible. The next generation of coils was the electrolytic detachable coils by Guglielmi (GDC). Now, there is a vast range of coils that can also be detached mechanically, and the fact that coils can be repositioned, retrieved or changed is a great advantage, especially if the coil is not at the desired position or not of the optimal size. In addition to the originally bare coils, hydro coils, liquid coils, fiber coils, and bioactive coils are all different types of coils currently available. Moreover, unique sizes, flexibilities, shapes, and forms are available, from very large coils, volume coils to very small, soft coils. Coils are mostly used for the endovascular treatment of intracranial arterial aneurysms, not typically used to occlude AVM feeders. However, they may be useful for slowing flow within a particular compartment of certain AVF and thus, to facilitate subsequent use of a liquid embolic agent. Detachable coils are also used for vessel occlusion, like in deconstructive therapy, and the transvenous approach to dural AVF and VGM.
Concerning solid agents, one must certainly mention the novel and very promising device, the Woven Endobridge ® (WEB II ) for intracranial aneurysm treatment. The WEB ® II is a self-expanding, nitinol, mesh device designed to achieve aneurysm occlusion after endosaccular deployment. Preliminary results from the WEBCAST trials have been very promising [26]; nonetheless, long-term results, especially concerning aneurysmal regrowth, are still lacking. Parent artery sacrifice is a valuable tool in the treatment of select vascular lesions. With detachable balloons no longer being available in many countries, most sacrifices are performed with primary coil embolization. However, traditional coil embolization as the primary means of parent artery sacrifice can be expensive, with high radiation expo® sure. A new hybrid coil, the Penumbra occlusion device (POD), was designed specifically to achieve occlusion in relatively large arteries, such as the carotid or vertebral artery [27]. The conclusions of a feasibility study in a swine ® model was that a carotid artery sacrifice using a novel POD ® device was safe and effective. Furthermore, the POD significantly reduced radiation and material costs compared with the other described endovascular techniques. Another ® new occlusion device on the market is the MVP (micro vascular plug system). It was designed to occlude vessels quickly with a single re-sheathable device. With regards to coil technology in the context of these new tools, one may wonder what future investigations will show. Especially in the nanotechnology era, perhaps further improvement of coils, making them more suitable, softer and smaller, will ® take place. New liquid embolic agents, like PHIL (precipitating hydrophobic injectable liquid), seem to be promising. ® As the suspended micronized tantalum powder in Onyx is ® responsible for its dark color, PHIL may be a truly viable alternative option as no tantalum powder is used for radiopacity. Thus, it may be favored for the treatment of visible superficial head and neck vascular malformations. The preliminary results from studies with another new liquid ® embolic agent called Squid demonstrated that the agent behaved safely and effectively in treatment of cerebral AVMs, AV fistulas, tumors, and aneurysms with satisfactory ® ® obliteration rates [28]. However, both PHIL and Squid are liquid embolics on the basis of ethylene-vinyl alcohol ® copolymer like Onyx . Ultimately, as rapidly as INR is growing, further research and development of more sophisticated devices and embolic agents is warranted and obligatory for continued progress in the field (Fig. 3).
Particles Particles like PVA are mostly used for the preoperative embolization of highly vascularized tumors to diminish the perioperative bleeding risk and induce tumor necrosis. They are available in 50–1000 μm sizes. Based on their composition and size, particles do not reach and bridge the fistulous connections in AVM with their inflow zone, nidus, and outflow zone. They may, though, occlude arterial feeders at the inflow zone. With the expected vessel recanalization after PVA embolization, they are no more eligible for treatment of AVM. However, they continue to have a strong relevance for the endovascular treatment of epistaxis. Ethanol Ethyl alcohol (98 % ethanol) and polydocanol are sclerosing agents that produce no immediate mechanical embolization but a severe inflammatory reaction because of cytotoxicity. Strong alcohol injections play an important role in the treatment of venous and lymphatic malformations by direct puncture, also known as sclerotherapy. There is little relevance for the use of ethanol in AVM due to its extremely high complication rates.
Acknowledgment The authors would like to thank Jacqueline Dornbusch for carefully reading the manuscript.
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Fig. 3 a Shows Ethibloc®, a protein derived from maize and dissolved in alcohol, that precipitated, while acrylates polymerizes in contact with blood. Note its yellowish-white colour. Depending on the particular pathophysiology, Ethibloc® has been diluted with Lipiodol or with Lipiodol and additional alcohol [21]. b Shows Onyx®, a liquid embolic
material consisting of ethylene-vinyl alcohol copolymer, available in various concentrations dissolved in dimethyl sulfoxide (DMSO) and suspended micronized tantalum powder to provide contrast for fluoroscopy. The tantalum is responsible for its dark colour
Financial Disclosure The authors have no financial relationships relevant to this article to disclose.
10. Wallace S, Gianturco C, Anderson JH, Goldstein HM, Davis LJ, Bree RL. Therapeutic vascular occlusion utilizing steel coil technique: clinical applications. AJR Am J Roentgenol. 1976;127(3):381–7. 11. Halbach VV, Higashida RT, Hieshima GB, Hardin CW, Pribram H. Transvenous embolization of dural fistulas involving the cavernous sinus. AJNR Am J Neuroradiol. 1989;10(2):377–83. 12. Guglielmi G, Viñuela F, Sepetka I, Macellari V. Electrothrombosis of saccular aneurysms via endovascular approach. Part 1: electrochemical basis, technique, and experimental results. J Neurosurg. 1991;75(1):1–7. 13. Hilal SK, Michelsen JW. Therapeutic percutaneous embolization for extra-axial vascular lesions of the head, neck, and spine. J Neurosurg. 1975;43(3):275–87. 14. Berenstein A, Kricheff II. Catheter and material selection for transarterial embolization: technical considerations. II. Materials. Radiology. 1979;132(3):631–9. 15. Berenstein A. Flow-controlled silicone fluid embolization. AJR Am J Roentgenol. 1980;134(6):1213–8. 16. Lins E, Wappenschmidt J. Zur Informationsbreite und therapeutischen Anwendung der selektiven Carotis externa-Angiographie bei malignen Prozessen des Gesichtsschädels. Laryngol Rhinol Otol (Stuttg.). 1976;55:62–65. 17. Brassel F, Solymosi L. An unusual congenital arteriovenous fistula of the vertebral artery and its embolization by a detachable balloon catheter. Neurosurg Rev. 1988;11(1):99–101. 18. Brassel F, Dettmers C, Nierhaus A, Hartmann A, Solymosi L. An intravascular technique to occlude the middle cerebral artery in baboons. Neuroradiology. 1989;31(5):418–24. 19. Voigt K, Djindjian R. [Diagnostic and therapeutic results of superselective cerebral angiographies in pathologic lesions in the vascular area of the human external carotid artery (author’s transl)]. Radiologe. 1976;16(10):436–43. 20. Kühne D, Helmke K. Embolization with “Ethibloc” of vascular tumors and arteriovenous malformations in the head and neck. Neuroradiology. 1982;23(5):253–8. 21. Brassel F. Entwicklung und Erprobung eines Gefäßmodells zur Simulation einer Embolisation mit Ethibloc® bei spinaler duraler arteriovenöser Malformation. Bremen: H.M. Hauschild GmbH; 1997.
Funding Source No external funding was secured for this study. Conflict of Interest On behalf of both authors, the corresponding author states that there is no conflict of interest.
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7 26. Pierot L, Spelle L, Costalat V, Szikora I, Klisch J, Herbreteau D, Holtmannspoetter M, Weber W, Liebig T, Cognard C, Bonafé A, Moret J, Byrne J, Molyneux A. WEB Flow Disruption: Preliminary Results from WEBCAST trial. J Neurointerv Surg. 2014;6(Suppl 1):A51. doi:10.1136/neurintsurg-2014-011343.96. 27. Spiotta AM, Turner RD, Chaudry MI, Turk AS, Hui FK, Schonholz C. Carotid sacrifice with a single Penumbra occlusion device: a feasibility study in a swine model. J Neurointerv Surg. 2014. pii: neurintsurg-2014-011461. doi:10.1136/neurintsurg-2014-011461. 28. Akmangit I, Daglioglu E, Kaya T, Alagoz F, Sahinoglu M, Peker A, Derakshani S, Dede D, Belen D, Arat A. Preliminary experience with squid: a new liquid embolizing agent for AVM, AV fistulas and tumors. Turk Neurosurg. 2014;24(4):565–70.
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