Preoperative Embolization of Cerebral Arteriovenous Malformations with Onyx

Patient Selection

Between January 2005 and January 2008, a total of 107 patients were treated with various modalities for cAVMs at our institution. Patients with the diagnosis of a cerebral arteriovenous fistula are not included. Open surgical resection as definitive treatment was the most common treatment choice (65 patients [61%]). If preoperative imaging suggested a good possibility of early surgical control of feeding vessels, and/or the location and size of the AVM was favorable, surgical resection was performed without preoperative embolization in 15 patients (14%). In more complex AVMs with higher Spetzler-Martin grades (SMGs), preoperative embolization was used in 47 patients (44%). In 3 patients (3%), a small residual AVM after surgical resection was treated with the gamma knife. Small AVMs, particularly in deeper locations, were primarily treated with the gamma knife in 26 patients (24%). Some smaller AVMs with fistulous components were occasionally treated with embolization only (7 patients [7%]) or in combination with the gamma knife (9 patients [8%]).

After its approval by the FDA, Onyx quickly became the primary embolic material for the treatment of cAVMs because of its ease in handling and superior control, with the exception of fistulous components, where we often prefer n-butyl cyanoacrylate (n-BCA). As a consequence, 41 of the 107 patients underwent embolization with Onyx alone or in conjunction with other materials in a total of 82 separate stages. We identified patients retrospectively by reviewing hospital charts. Data on patient demographics, AVM characteristics, and endovascular procedures before surgery were analyzed. Approval of this study was granted by the Institutional Review Board following the standard protocol for retrospective reviews of patient charts and electronic records in accordance with the Health Insurance Portability and Accountability Act.

Patient and AVM Characteristics

The patients (n = 41) were relatively young with a median age of 41 years (age range, 12–62 years). The female sex was predominant (male-to-female ratio, 15:26). Nineteen patients (46%) presented with an intracerebral hemorrhage caused by the malformation. The remaining patients presented with seizures and/or headaches. The malformations were located supratentorially in 88% (36 patients). In 19 patients (46%), the lesion was left sided; the lesion was located in the midline in 2 patients (5%). Eloquent brain⁵ was involved in 31 patients (77%). Mean maximal diameter of the cAVM nidus was 3.71 ± 1.55 cm. The measurements of the maximum AVM diameter were based on diagnostic imaging including angiograms, MR imaging, and CT scans. We measured the postembolization maximal cAVM diameter using the relative maximal diameter change as observed by comparison of preembolization and postembolization arteriograms and absolute measurements of the maximal preembolization diameter by CT or MR imaging. The average volume reduction of the cAVM was analyzed in categories according to Weber et al⁷ in reference to the postembolization angiogram. Deep venous drainage was present in 22 patients. Median preoperative Spetzler-Martin grade (SMG) was III (range, I–V). Three patients presented with an SMG I cAVM, 14 patients with an SMG II cAVM, 15 patients with an SMG III cAVM, 7 patients with an SMG IV cAVM, and 3 patients harbored an SMG V cAVM. Demographics and AVM characteristics are summarized in Table 1.

Interventions

In 41 patients, a total of 82 separate embolization procedures were performed. Onyx was used in all 82 embolizations, either as the sole agent (62%) or in conjunction with other materials (38%) such as polyvinyl alcohol particles, detachable coils, and n-BCA. On the basis of preembolization arteriography information, the goal of the embolization was “cure” in only a few cases. Instead, the treatment intent was to reduce the flow in the cAVM by occlusion of feeding arteries while preserving the draining veins to reduce the risk and increase the success of a subsequent treatment, typically surgery. A median of 2 embolization procedures was performed per patient (range, 1–5). Most the patients (29 patients [71%]) then underwent surgical resection of the cAVM. Six patients (15%) were treated with stereotactic radiosurgery. Four patients (8%) did not yet receive additional treatment.

Statistics

We performed the statistical analysis using the statistics program SPSS 15.0 (SPSS, Chicago, Ill). Patient demographics, cAVM characteristics, endovascular procedures, results, and complications were described for all patients. Frequency and percentage values of categoric variables as well as median and range of continuous variables were determined. We compared data using the paired t test, Wilcoxon test, and χ² test. A probability value of less than 5% was considered significant.

Morbidity and Mortality Rates after Preoperative Embolization with Onyx

Various studies have investigated the morbidity and mortality rates associated with preoperative cAVM embolization before the introduction of Onyx.^1,4,8-12 At that time, the morbidity and mortality rates with preoperative embolization ranged from 3.8% and 1.0% to 28% and 3.7%, respectively. Similar to other investigators, with use of Onyx, our results of a permanent morbidity rate of 12.2% and no deaths after preoperative Onyx embolization are within that range (Table 3). Ann H. Costello and Judy Chen presented clinical data regarding Onyx embolization collected from 17 centers (including Dallas) at the Neurologic Devices Advisory Panel Meeting on August 5, 2003 (http://www.fda.gov/OHRMS/DOCKETS/AC/03/slide/3975s1–02-fda.ppt). In this unpublished study, 51 patients were treated with Onyx embolizations of cAVMs. The observed stroke rate was 4.3%. The mortality rate documented in this analysis was 4.3% as well. The only experimental study from a single North American center was published by Jahan et al¹³ in 2001. They found a permanent morbidity rate of 4% in 23 patients treated. In their series, there were no deaths. Other similar results are documented by Mounayer et al¹³ in 2007 in a series of 94 patients. They described an overall morbidity rate of 8.5% per patient and a mortality rate of 3.2%. Hamada et al¹⁵ documented a morbidity rate of 5.3% in a series of 57 patients, with no deaths occurring. van Rooij et al¹⁶ experienced a morbidity rate of 4.6% per patient and a mortality of 2.3%. Two additional studies with contradictory results have been published by Weber et al.^7,17 In the first study, Weber et al examined the morbidity rate in 93 patients treated with Onyx for cAVMs, which apparently was 12% per patient, with no deaths. In a second consecutive study with 47 patients, they documented an even higher morbidity rate of 28%. The results of the second study seem less representative because the observed high morbidity rate of 28% is not only in contrast to the authors’ own experience but also the other published and unpublished data presented above. In summary, the morbidity and mortality rates of preoperative Onyx embolization of cAVMs may be similar to the morbidity and mortality rates of embolization before the introduction of Onyx (overall range, 10% per patient [5% per procedure]).

Volume Reduction

Volume reduction is difficult to measure precisely. Unlike selective angiography, CT, MR imaging, or CT angiography allows depiction of the entire nidus with injection of all feeding vessels simultaneously. Furthermore, with CT, CT angiography, or MR imaging, no calibration is required to determine precise dimensions. However, the resolution of the angio-architecture details is inferior compared with standard angiography. Finally, measurements of a diffuse nidus may vary considerably depending on the investigator. Possibly because of these limitations, some studies with Onyx did not present precise measurements regarding volume reduction.^14-16 We measured the volume reduction of the cAVM postembolization in categories according to Weber et al^7,17 They calculated the AVM volume on the basis of standard arteriography with the formula suggested by Pasqualin et al¹⁸: V = ½ × w × h × l [V ∼ volume, w ∼ width, h ∼ height, l ∼ length]. Volume reduction was then determined on the basis of postembolization angiography. Weber et al^7,17 achieved an 80% to 84% volume reduction with a considerably high morbidity rate. In their presentation, Ann H. Costello and Judy Chen quote a volume reduction of ≥ 50% in 97.6% (41/42) of the patients after embolization with Onyx compared with 84.3% (43/51) with n-BCA (unpublished data). Jahan et al¹³ reported an average volume reduction of 63% with a low morbidity rate and no deaths. On the basis of these reports, a volume reduction of 50% to 65% may be a desirable target with acceptable associated morbidity and mortality rates. The addition of Onyx to the endovascular armamentarium seems to improve occlusion rates.

“Cure”

Complete occlusion of a cAVM without recurrence on follow-up angiography may represent a “cure.”^14,19 A prerequisite for “cure” is the complete occlusion of the draining veins. However, the primary principle of “preoperative” embolization is the preservation of the draining veins because the risk for hemorrhage increases with partial embolization and obstructed venous outflow.^13-16 As a consequence, a “cure” may occur either as the result of the planned sacrifice of the venous outflow in small cAVMs or is accidental with increased risk for the patient. With 2 competing goals, sacrifice of the draining vein(s) for cure versus preservation of the venous outflow with size reduction in preparation for additional treatment, the reported “cure” rates between different centers varies considerably (from 0% to 28%).^7,13-17,19 At our institution, “cure” is typically not the goal of the preoperative embolization. Complete occlusion of the cAVM was achieved in 10%. Half of these patients were found to have recurrence of cAVM during follow-up and then underwent surgery. Therefore, our “cure” rate was only 5%. Mounayer et al¹⁴ as well as Katsaridis et al¹⁹ achieved the highest percentage of “cure,” both in 28%. Mounayer et al¹⁴ report a morbidity rate of 8.5% and a mortality rate of 3.2%, respectively. Katsaridis et al¹⁹ document a similar morbidity rate with 8% and a mortality rate of 3%. It is noteworthy that a higher cure rate as a result of more aggressive embolization may be associated with a higher mortality rate. However, no final conclusions can be drawn at this point. Additional experience with Onyx and long-term follow-up of “cured” cAVMs is required to determine the value of complete cAVM occlusion after embolization as stand-alone treatment.

Definitive Treatment

Surgical resection of the cAVM with or without preoperative embolization is the most definitive treatment of cAVMs with total removal of the lesion.^1,4-6,8-12 Accordingly, surgery was performed as definitive treatment after preoperative Onyx embolization in more than 50% of the study patients in 5 of 7 centers.^7,13-17 However, with improving obliteration rates with Onyx and/or n-BCA, radiosurgery is more frequently used as an alternative “definitive” treatment for small residual cAVMs.^13,14,16 Jahan et al¹³ treated 48% of their patients with radiosurgery after embolization. At the time of the report, they had limited follow-up and documented complete occlusion after 20 months in only 1 patient. van Rooij et al¹⁶ treated 45% of their patients with radiosurgery after Onyx embolization. There were 5 of 20 patients who had confirmed cAVM occlusion on follow-up arteriograms; the other 15 patients were still pending follow-up. Mounayer et al¹⁴ treated 20 patients with radiosurgery as well but did not quote any occlusion rates. Our patients treated with radiosurgery are awaiting follow-up as well. In summary, embolization with Onyx followed by radiosurgery is a promising concept. More clinical data will be necessary for a more definitive analysis. Surgical resection remains the reference standard for residual cAVM after embolization.