Embolization of cranial dural arteriovenous fistulae with ONYX: Indications, techniques, and outcomes

Objectives: The purpose of this study was to establish the role of the liquid embolic agent, ONYX, in the treatment of cranial dural arteriovenous fistulae (DAVFs) and to redefine the indications, techniques and outcomes of treatment with ONYX. Materials and Methods: This is a retrospective study of 25 DAVF patients who underwent endovascular treatment with ONYX between February 2006 and July 2008. All patients of DAVF presenting in this period were treated with ONYX. Results: Anatomic cure (i.e., complete angiographic closure of the fistula) was achieved in a single session and through a single arterial pedicle injection in 21 out of 25 patients (cure rate of 84%). Out of four patients with residual fistulae, one achieved cure that was evident on a control angiogram obtained at 3 months while three had no vascular access for further embolization and so were referred for radiosurgery. There was only one recurrence seen in angiograms obtained at the end of one year and this patient was re-embolized successfully with ONYX. Complications were seen in two patients. Conclusion: ONYX embolization of DAVFs has revolutionized the endovascular treatment of DAVFs, achieving high cure rates in a single session with minimal complications. Transarterial ONYX embolization should be the first option for all locations, except cavernous DAVFs.


Introduction
Intracranial dural arteriovenous fistulae (DAVFs) are uncommon lesions that reportedly account for 10-15% of all intracranial arteriovenous lesions.Most of these lesions are acquired, and venous sinus thrombosis, previous surgery, ear infection, and head trauma are potential predisposing factors. [1,2]8] DAVFs that drain retrogradely into cortical veins are aggressive lesions that can present with intracranial hemorrhage, seizures, intracranial hypertension, and neuropsychiatric symptoms. [9]Other features suggestive of the aggressiveness of DAVFs are stenosis of the draining sinus, deep venous drainage, certain locations like the anterior cranial fossa and tentorium, venous congestion and venous aneurysm or varix, mainly in those DAVFs with direct leptomeningeal venous drainage. [10]Intolerable bruit and DAVFs of the cavernous sinus that present with ocular symptoms, are also indications for treatment, even without cortical venous refl ux.Isolated sinuses with DAVFs are extremely aggressive lesions due to extensive cortical venous refl ux.Prompt and defi nitive treatment is indicated for these lesions.Endovascular management is now the primary modality of treatment for all DAVFs.There have been rapid advances in endovascular techniques, hardware, and in the strategies of treatment 2008.The treatment criteria included aggressive symptoms (hemorrhage, neurological defi cit, cortical venous refl ux, direct leptomeningeal venous drainage) and intolerable benign symptoms like bruit or severe headaches.Table 1 represents the clinical presentations of the DAVFs as per their locations.DAVFs of the cavernous sinus, mainly of the anterior compartment with good transarterial access, were also treated with ONYX embolization.There were 23 males and two females whose age ranged from 12 to 68 years.The locations of the fi stulae in these 25 patients were: Transverse sigmoid ( 9), all left sided, tentorial (3), anterior cranial fossa (2), cavernous sinus (2), foramen magnum (3), sphenoid (1), petrosal (1), sigmoid sinus (1), middle cranial fossa (2), and frontal intraosseous (1).Three patients had a prior history of venous sinus thrombosis and one patient reported a history of head trauma in the past while one was incidentally diagnosed when evaluated for ischemic stroke.
Cortical venous refl ux was seen in 17 patients and direct leptomeningeal venous drainage was seen in four patients.One patient had a middle cranial fossa DAVF draining into the superior ophthalmic vein, leading to ocular symptoms.Three patients had an osteodural type of DAVF.One patient with a foramen magnum DAVF showed refl ux into the perimedullary venous system.All patients with foramen magnum and petrosal DAVFs showed direct drainage into the leptomeningeal veins with venous pouches, which then refl uxed into multiple cortical veins.Four out of nine patients with transverse sigmoid DAVFs had an isolated sinus.One transverse sigmoid DAVF patient had been embolized previously with transvenous coiling and one patient with an osteodural sphenoid wing DAVF had undergone two sessions of transarterial glue embolization previously.

Clinical presentation
Intracranial hemorrhage was the presenting symptom in 12 out of 25 patients (48%).Nine out of these 12 had intracerebral hemorrhage (ICH), with subarachnoid hemorrhage (SAH) in three patients.Among the ICH patients, transverse sigmoid sinus was the most frequent location followed by tentorial, anterior cranial fossa, petrosal [Figure 1], and osteodural sphenoid wing DAVFs.SAH was the predominant manifestation in foramen magnum DAVFs.Other presentations were headaches (76%), seizures (20%), tinnitus (16%), ocular symptoms (16%), neuropsychiatric symptoms (8%), and progressive neurodefi cit (8%).Two patients had neuropsychiatric symptoms and both showed extensive venous congestion [Figure 2] on angiography, with a fi stula in the left transverse-sigmoid location.One had features of chronic venous congestion on CT scan.One of these patients had memory disturbances and the other  Four patients had papilledema, two of whom presented with blurring of vision; all of them had transverse-sigmoid DAVFs.Four out of nine patients with transverse-sigmoid DAVFs and one patient with an anterior superior sagitt al sinus DAVF had an isolated sinus, and all presented with ICH.Eight out of nine patients with transverse-sigmoid DAVFs had thrombosis of the sigmoid sinus evident on MRI or angiography.One case with torcula and medial transverse sinus DAVF had no cortical venous reflux, although intracranial hypertension was present as evidenced by bilateral papilledema.One patient with a sigmoid DAVF presented with intolerable bruit although there was no cortical venous refl ux (CVR).

Treatment strategy
Endovascular treatment is the primary modality of treatment of all DAVFs at our center for complete cure.
The liquid embolic agent, ONYX (ethylene vinyl alcohol copolymer, ev3), was used for treatment in all the patients.ONYX is available in two concentrations ONYX 34 (more viscous) and ONYX 18. Six-vessel angiography was performed in all patients to study the angioarchitecture of the shunt precisely and to plan the treatment.

Endovascular procedure/technique
Angiography and embolization were performed on a biplane angiographic unit (Integris Allura, Philips Medical Systems).Treatment was done under general anesthesia and systemic heparinization.A 5F guiding catheter was used for the external carotid artery (ECA) and 6F for the internal carotid artery (ICA) and vertebral artery (VA).
Dimethyl sulfoxide (DMSO) compatible microcatheters (Ultrafl ow, Marathon, Echelon, Rebar,ev3) were used for superselective cannulation of the predominant feeding arteries.Microguidewires used were Mirage or X-Pedion (ev3).The microcatheter was positioned at the fistula site as close to the draining sinus or vein as possible.
A microcatheter angiogram was taken to confirm the position of the catheter and to see the drainage of the fi stula.
The microcatheter was fl ushed with 10 mL of normal saline and the dead space was fl ushed with 0.25 mL of DMSO injected slowly over 40 sec.The ONYX vial was shaken on the ONYX mixer for at least 20 min prior to its use.The ONYX injection was then started slowly-initially 0.2 mL without guidance and subsequently under biplane roadmap guidance.Injection was stopped for a few minutes when the initial refl ux on the microcatheter was seen to form a plug.Whenever reflux occurred, injection was stopped for sometime.Patience during injection is the key to achieve cure with ONYX.Embolization was performed until angiographic cure was achieved [Figure 3].The microcatheter was withdrawn rapidly at the end of each procedure.Postoperative anticoagulation was done only in patients with marked stasis or slow fl ow in cortical veins.
During embolization through the ascending pharyngeal artery, care was taken to remain as close to the fi stula as possible to minimize ischemic injury to the cranial nerves.Embolization through transosseous branches of the occipital artery required a lot of patience and a large volume of ONYX as ONYX penetration starts only aft er 25-30 minutes.
Protective balloons should be used in cases with high-fl ow DAVFs with large supplies from the vertebal or the internal carotid arteries.Flow control can be achieved with manual compression of the carotids or both the jugular vein and the carotid, or by balloon occlusion of the venous sinus.In highfl ow DAVFs, the injection should be started with ONYX 34 and, if needed, continued with ONYX 18. Refl ux on the microcatheter is not much of a problem in embolization through the ECA branches.

Results
The results of the study have been recorded in terms of the location, clinical presentation, angiographic outcome and complications [Table 1].Also the volume of ONYX injected and the duration of injections were recorded.All embolizations were transarterial.
In 21 out of 25 patients, angiographic cure (i.e., complete closure of the fi stula) was achieved in a single session and through a single arterial pedicle injection.In only one patient with a high-fl ow torcula and a medial transverse sinus DAVF with multiple feeders, were two sessions performed and four arteries were embolized.A slow-fl ow residue was seen at the end of the last session and also in the one-year follow-up angiography.The remaining three who had slow-fl ow residual fi stulae did not have access for further embolization and hence, were referred for radiosurgery.Flow control was achieved in one patient with a left transverse-sigmoid DAVF by balloon placement in the transverse sinus.In two patients with high-fl ow DAVFs, balloons were placed in the internal carotid artery and the vertebral artery [Figure 4] respectively, to prevent the refl ux of ONYX into these arteries that were supplying the fi stulae through their meningeal branches.In both the patients of isolated TS DAVFs, cure was achieved through a single pedicle injection.
A total of 28 arteries were embolized: The middle meningeal artery in 17, the occipital artery in four, distal branches of the internal maxillary artery in three, the ascending pharyngeal in two, the ophthalmic artery in one, and the dural branch of the VA in one.Embolization of only one feeder was performed in 24 out of 25 patients.The volume of ONYX injected ranged from 0.4 to 5 mL per procedure.The duration of injection per pedicle ranged from 15 to 90 min.The duration of injection was longer in transosseous branches of the occipital artery and the volume of ONYX used was also higher.In high-fl ow situations, the initial injection was done with ONYX 34 (volume ranging from 0.5 to 1.5 mL) and then continued with ONYX 18.In one patient with a high-fl ow cavernous DAVF, one coil was placed initially and then embolization was performed using ONYX 34.
All patients were extubated postoperatively and careful observation was done in the Intensive Care Unit for 24 h.Only one patient was electively ventilated for 24 h as there was marked stasis in the congested veins aft er closure of the fi stula.Anticoagulation was done for 48 h.Patients were followed up at one month and at three and six months with cerebral angiography and MRI respectively.Control angiography was performed six months post procedure in 20 patients of whom 16 showed complete cure; a control angiogram is awaited in fi ve patients.Clinically, all the patients had resolution of symptoms aft er the procedure and in the follow-up period (including those with residual fi stulae).
The cure rate for DAVFs with ONYX embolization was 84% with stable occlusion of the fi stula as seen on control angiograms.

Complications
Two patients had complications aft er treatment: In one patient, a venous pouch was present at the cerebellopontine angle which thrombosed aft er fi stula closure, causing a mass effect.Surgical decompression was done and the postoperative course was uneventful.One patient with a cavernous dural fi stula developed a left parietal hematoma within 24 hours of the procedure.However, good clinical recovery was observed.Only one patient with a high-fl ow TS DAVF with features of chronic venous congestion prior to the procedure, had long-term morbidity and a poor outcome.
One patient with a right frontal intraosseous DAVF (a case of CAMS II) had ICH one year later due to the temporal AVM; no residual fi stula was seen.

Discussion
Dural AVFs are uncommon intracranial lesions consisting of direct, abnormal connections between the meningeal arteries and the dural venous sinuses or leptomeningeal veins.Their symptoms are highly variable.Various studies have shown a strong correlation between the associated aggressive symptoms and the presence of cortical venous refl ux .The aim of the treatment should be complete closure of the shunt by occluding the proximal vein or the diseased sinus if it is not taking part in the drainage of the brain.
The treatment options available are surgery, radiosurgery, [11] and embolization. [12]There have been technical advances in all the fi elds with improving cure rates over the last two decades.
A multidisciplinary approach was used initially for complex DAVFs. [13,14]Surgery and radiosurgery have shown mixed results. [15,16]The results of embolization have improved over time due to rapid advancements in endovascular techniques (highly fl exible hydrophilic catheters, wires, and advanced embolic agents).Mullan et al. [17] fi rst described embolization of a DAVF of the cavernous sinus in 1979.Hallbach et al. [18] (1987) fi rst reported transvenous embolization of a transversesigmoid DAVF.With advances in microcatheters, microwires, and coils, transvenous embolization became the treatment option for these locations. [19,20]Transarterial embolization was performed with polyvinyl alcohol (PVA) particles to resolve symptoms or in combination with other procedures such as irradiation, surgery, or transvenous embolization.Complex dural fi stulae were still diffi cult to treat, especially those in which the sinuses were thrombosed distally as well as proximal to the fi stulous segment, also known as an isolated sinus.Transosseous direct puncture and packing of the isolated sinus have been established as primary treatment options in isolated sinuses with DAVFs. [21,22]In DAVFs with direct leptomeningeal venous drainage and in some cases of cavernous DAVF (mainly the anterior compartment ones), treatment with dilute N-Butyl cyanoacrylate (NBCA) has shown good results. [23]The drawbacks of NBCA [35] use are the need for a highly experienced operator, appropriate glue concentrations, and unpredictable outcomes (too proximal or too distal embolisation lead to hazardous complication or incomplete fi stula closure).Recent studies have reported the use of ONYX by the transvenous route for cavernous dural fi stulae. [24]Surgery and radiosurgery are used these days only in those patients with endovascular treatment failure.
The advent of a new liquid embolic system, ONYX (ev3), with its unique physical properties has revolutionized endovascular treatment of intracranial DAVFs.ONYX is a nonadhesive liquid embolic agent comprising of an ethylene vinylalcohol copolymer dissolved in DMSO with tantalum powder for radio-opacity.[27][28] The refl uxhold-reinjection technique allows highly predictable and thorough penetration, especially of multiple microfi stulae along the wall of the sinus supplied by multiple feeders.The excellent endovascular handling characteristics of ONYX allow complete occlusion of the diseased sinus or proximal vein without refl ux into the cortical veins, thus minimizing complications [Figure 5].The injection can be interrupted and guiding catheter contrast injections can be done to assess the completion of the procedure, which is not possible with NBCA.Two concentrations of ONYX are available at our center, ONYX 18 and ONYX 34.The lower the concentration of the polymer, the more is the distal penetration achieved.Placing the ONYX vial on an ONYX heater for 5-10 min at 70ЊC before injection, may further enhance penetration and fl ow of ONYX.ONYX is a permanent agent that has not been found to cause much infl ammation in animal studies, hence, long-term or permanent cure is expected. [29,30]In this study of 25 patients, 17 had cortical venous refl ux and four had direct leptomeningeal venous drainage.The remaining four had intolerable bruit or ocular symptoms.Intracranial hemorrhage was the predominant presenting symptom.In 21 out of 25 cases, complete closure of the fi stula by ONYX embolization was achieved in a single injection from a single feeder, thus achieving a cure rate of 84%.
The maximum duration of injection was 90 min with easy retrievability of microcatheters at the end of the injection in all cases Two cases of isolated sinus were eff ectively treated with ONYX embolization in a single session, thus obviating the need for direct puncture and packing of sinuses which is cumbersome and time consuming.
Postprocedure complications were noted only in two patients, of which one patient with a cavernous DAVF had a small parietal hematoma distant from the fi stula site, and the other had thrombosis of the venous pouch which was successfully managed with surgical intervention.Good outcome is not expected in patients presenting with chronic venous congestion.In patients with extensive cortical venous refl ux and venous congestion of the brain, the closure of the fi stula increases the propensity of thrombosis of these arterialized cortical veins.These patients should be managed with low molecular weight heparin for at least 48 hours aft er the procedure.
Various case reports in the last two years have described the effi cacy of transarterial ONYX embolization in DAVFs of the anterior cranial fossa, superior sagitt al sinus, lesser sphenoid wing, clival DAVFs, and in the isolated sinus. [31- 34]n their study of six DAVF patients who were treated with ONYX, Tulgoat et al. [35] stated that ONYX 18 is a safe treatment and when performed in optimal conditions, fi lls the total DAVF and its drainage vein or sinus aft er a single arterial feeder catheterization.Nogueira et al. [36] performed a retrospective analysis of 12 consecutive patients with intracranial DAVFs who were treated with ONYX as the single treatment technique.Cure was noted in ten out of 12 patients; there was no signifi cant morbidity or mortality.They concluded that endovascular treatment of intracranial DAVFs with ONYX is feasible, safe, and highly eff ective with a small recurrence rate in the short-term follow-up.Carlson et al. [37] reported a series of six patients with symptomatic DAVFs who were treated initially with transarterial ONYX embolization and other endovascular techniques and achieved cure in fi ve patients.None of the patients had worsening of neurological function.They concluded that transarterial ONYX embolization and other endovascular methods can angiographically obliterate DAVF and even allow occlusion of multiple arterial feeding arteries from a single arterial injection.Cognard et al. [38] performed a study of 30 patients of DAVF with cortical venous refl ux (CVR), who had been treated with ONYX embolization.Cure rate aft er embolization with ONYX was 80% (24 out of 30 patients) and complications occurred in two patients.

Conclusion
This study emphasizes the role of ONYX in the treatment of intracranial DAVFs.ONYX has unique physical properties, which facilitates prolonged injections that can be bett er controlled, and have a more predictable penetration.
Transarterial ONYX embolization should be the first option for all locations, except cavernous DAVFs.ONYX embolization of an isolated sinus with DAVF should replace direct puncture and packing of sinuses.To conclude, ONYX embolization has revolutionized the endovascular treatment of DAVFs, achieving higher cure rates in single sessions with minimal complications.With our experience of ONYX, we recommend ONYX as the primary treatment modality in DAVFs of all locations, except cavernous DAVFs.

Figure 1 (Figure 2 (
Figure 1 (a-f): Left petrosal dural arteriovenous fi stula (AVF).CT scan of the brain (a) shows left parieto-occipital hemorrhage with intraventricular extension Left external carotid angiogram (b) shows a left petrosal dural AVF (arrow).Left external carotid angiogram (c) with a road map image shows the fi nal position of the microcatheter (arrow) in the middle meningeal artery.Microcatheter angiogram (d) shows the isolated petrosal sinus (arrow) with extensive cortical venous refl ux (arrowheads).2 mL of Onyx 18 was injected from this site over 40 min.Postembolization left common carotid angiogram (e) shows exclusion of the fi stula.Plain skull radiograph (f) shows the Onyx cast (arrow)

Figure 3 (
Figure 3 (a-d): Left transverse dural arteriovenous fi stula (AVF).Lateral (a) and oblique (b) left occipital angiograms show a left transverse dural AVF (arrow).Transarterial embolisation was performed through the occipital artery with ONYX.Postembolization left common carotid angiogram (c) shows occlusion of the fi stula.Plain radiograph (d) shows the ONYX cast (arrows)

Figure 4 (
Figure 4 (a-e): Foramen magnum dural arteriovenous fi stula (AVF).Right external carotid (ECA) (a) and right vertebral (b) angiograms show a foramen magnum dural arteriovenous fi stula which is supplied by branches from the ascending pharyngeal (arrow) and posterior meningeal (thick arrow) arteries.Right ECA angiogram shows refl ux into the spinal perimedullary venous system (arrowhead in (c).Embolization was performed through the ascending pharyngeal artery with balloon placement in the right vertebral artery arrow in (d).Post-embolization right ECA angiogram (e) shows obliteration of the fi stula

Figure 5 (
Figure 5 (a-f): Falco-tentorial dural fi stula.Frontal (a) and lateral (b) left external carotid angiograms show a high fl ow falco-tentorial dural fi stula (arrow) supplied by the middle meningeal artery (arrowhead).Road map image (c) shows the position of the microcatheter (arrow) in the distal middle meningeal artery close to the venous pouch.Postembolization left common carotid angiogram (d) shows complete closure of the fi stula.The Onyx cast arrow in (e) is seen with penetration into the venous pouch.Lateral left ECA angiogram (f) obtained after six months shows no evidence of the fi stula