Abstract
This study investigated the effect and safety of targeted embolization in partially embolized cerebral arteriovenous malformation (AVM) followed by gamma knife surgery (GKS). We retrospectively analyzed 86 AVM patients who were targeted embolized by Onyx followed by GKS for residual nidus. Embolization-related complications were collected and the clinical effect was evaluated. During targeted embolization, intranidus or hemodynamic aneurysms and AVM-related fistula were evaluated and targeted embolized. Patients with AVM-related aneurysms and fistula were divided into a targeted embolization group and non-targeted embolization group based on the retrospectively determined treatment strategy. The effect of targeted embolization on hemorrhage risk was evaluated. The overall annual hemorrhage rate was 1.66% with 2.26% for ruptured AVMs and 1.08% for unruptured lesions. The annual mortality rate was 0.4%. Only one in 16 patients with embolization-related complications had permanent neurologic deficit. Twenty-four of 29 cases with intranidus aneurysms were targeted embolized, four of five cases with hemodynamic aneurysms were targeted embolized and eight of nine cases with arteriovenous fistula were targeted embolized. Chi square results showed the hemorrhage complications in the target embolization group were significantly lower than those in the non-target embolization group (p < 0.01). Targeted embolization combined with GKS treatment decreased the annual hemorrhage rate and improved clinical outcome with low permanent complications in partially embolized AVMs. This method could be proposed for the treatment of large brain AVMs when a single-technique treatment is not feasible.
Keywords: Cerebral arteriovenous malformations, endovascular embolization, gamma, knife surgery, hemorrhage complication, targeted embolization
Introduction
With the development of material science and improvements in treatment technology, endovascular embolization has proved to be an effective and reliable method for cerebral arteriovenous malformation (AVM) treatment. It is common practice to reduce the volume of AVM by embolization and then undertake gamma knife surgery (GKS) for any residual nidus. However, the obliteration rate was low for GKS when prior embolization could not reduce AVM size to an optimal value. The goal for endovascular embolization should be clear when facing a large volume AVM that could not be obliterated by embolization alone. We use the “targeted embolization” method not only to decrease the AVM nidus, but also to deal with the most dangerous factors in AVM structure: aneurysms and fistula. By target embolizing the intranidus aneurysms, hemodynamic aneurysms and AVM-related high-flow fistula, we aim to decrease the hemorrhage risk, reduce blood flow and eliminate the “radiobiological resistance” effect of fistula, which will decrease the effect of GKS treatment.
Nowadays, the fluid embolization agent Onyx is widely used for AVM embolization. However, large cases with long-term follow-up of Onyx target embolization combined with GSK for residual nidus have seldom been reported. Our study retrospectively analyzed 86 patients treated by targeted Onyx embolization combined with GKS. We aimed to evaluate the effect and safety of targeted embolization for partial embolization combined with GKS treatment for cerebral AVM, and evaluate the effect of targeted embolization on hemorrhage complications.
Method
Patient population
Between April 2004 and September 2011, 86 patients’ clinical data were fully collected in the Interventional Neuroradiology Department of Tiantan hospital after partial target embolization with Onyx followed by GKS in our Gamma Knife Center, Beijing Neurosurgical Institute, Capital Medical University of China. The characteristics of the patients and AVM anatomy structure are summarized in Table 1. All the patients with less than two years of imaging follow-up were excluded from the analysis of total obliteration rate, with the exception of patients who demonstrated radiological evidence of total obliteration on digital subtraction angiography (DSA).
Table 1.
Characteristics of AVM patients.
| Characteristics | Value (%) |
|---|---|
| Sex | |
| Male | 44 (51.2) |
| Female | 42 (48.8) |
| Age at presentation (years) | |
| Mean | 27.8 |
| Median | 26.0 |
| Range | 8–51 |
| Location | |
| Cerebral lobe (frontal/temporal/ parietal/occipital) | 67 (77.9) |
| Corpus callosum | 5 (5.81) |
| Basal ganglia | 1 (1.16) |
| Thalamus | 3 (3.49) |
| Cerebellum | 8 (9.30) |
| Brainstem | 2 (2.33) |
| Depth | |
| Cortical | 46 (53.5) |
| Deep | 40 (46.5) |
| AVM volume (cm3) | |
| Mean | 24.24 |
| Median | 14.1 |
| Range | 0.75–115.38 |
| AVM size | |
| Small (<3 cm) | 18 (20.9) |
| Medium (3–6 cm) | 56 (65.1) |
| Large (>6 cm) | 12 (14.0) |
| Arterial pedicle feeders | |
| Single | 19 (22.1) |
| Multi | 67 (77.9) |
| Venous drainage | |
| Superficial venous drainage | 19 (22.1) |
| Deep and superficial venous drainage | 21 (22.4) |
| Deep venous drainage | 46 (53.5) |
| No. of draining veins | |
| Single | 36 |
| Multi | 50 |
| Presence of coexisting aneurysm | 34 (39.5) |
| Intranidus | 29 (33.7) |
| Hemodynamic | 5 (5.8) |
| Presence of coexisting fistula | 9 (10.5) |
| Presence of coexisting venous aneurysm | 19 (22.1) |
| Spetzler-Martin Grade | |
| I | 4 (4.7) |
| II | 23 (26.7) |
| III | 31 (36.0) |
| IV | 20 (23.2) |
| V | 8 (9.3) |
| Symptoms at first diagnosis | |
| Hemorrhage | 38 (44.2) |
| Hemorrhage+seizure | 5 (5.8) |
| Seizures | 23 (26.7) |
| Migraine/headache | 14 (16.3) |
| Others (cranial nerve deficits/hemiparesis/ hemiplegia/ dizziness/ visual deterioration) | 6 (7.0) |
| Asymptomatic | 1 (1.2) |
Targeted embolization procedure
The principle for targeted embolization was to eliminate the AVM-correlated aneurysms and fistula prior to GKS treatment. Targeted embolization provides a relative safe period for GKS to take effect. All procedures were performed with patients under general anesthesia using a biplane angiography system. A 6F sheath was placed in the femoral artery and a 6F guiding catheter inserted into the carotid artery or vertebral artery according to AVM anatomy. A flow-directed DMSO-compatible microcatheter (Marathon, UltraFlow, or Apollo; ev3) was navigated into the nidus. Superselective angiography was subsequently performed to precisely analyze the angioarchitecture of the nidus and the venous drainage, and to confirm the stable position of the microcatheter distal tip. When intranidal aneurysms or hemodynamic aneurysms were found by superselective angiography, they were targeted for embolization in the procedure. Onyx was used as the first-line embolic agent except in the case of high-flow direct fistulas or when the microcatheter was inserted in a short feeding pedicle. For Onyx embolization, the microcatheter was flushed with normal saline, and the dead space filled with DMSO (0.25 ml). Onyx was then slowly injected under subtracted fluoroscopic control. In the event of reflux or passage of Onyx in the draining veins, Onyx injection was interrupted for 30 seconds to two minutes and then restarted. At the end of the procedure, the microcatheter was removed by gentle traction. Staged sessions of embolization were usually performed to progressively reduce the size of the circulating nidus and induce moderate nidal and perinidal changes to avoid hemorrhagic complications. Treatment by embolization was interrupted when it was no longer possible to access the nidus or to inject Onyx into the nidus.
Radiosurgical procedure
Radiosurgery was performed with a Leksell Gamma Knife Perfexion™ (Elekta, Norcross, Georgia). The mean nidus volume was 9.95 cm3 (range 0.59--57.8 cm3) before GKS, the median margin dose (dose to the edge of the AVM nidus) was 16.3 Gy (range 13–21 Gy), the median central dose was 32.9 Gy (range 26–40 Gy).
Radiological and clinical follow-up
Patients underwent MR imaging every six months after GKS. Control DSA was performed two years after radiosurgery but was sometimes advanced or delayed according to MR imaging results. The MRI and DSA studies were performed at a combination of facilities including those at the interventional neuroradiology department of Tiantan hospital, Gamma Knife Center of the Beijing Neurosurgical Institute, and outside hospitals. All imaging studies were reviewed by three attending neurosurgeons and attending neuroradiologists of the Beijing Neurosurgical Institute.
Computed tomography or MRI was performed for neurological deterioration. Hemorrhage was defined by imaging studies. For the annual hemorrhage rate, the number of risk years was defined as the total time across all patients from radiosurgery to either obliteration or to last clinical follow-up in patients without hemorrhage. Patients were evaluated by DSA to confirm AVM obliteration only after MRI demonstrated absence of a residual lesion. Obliteration was defined by absence of abnormal arteriovenous shunting on DSA. Although DSA is the gold standard for evaluating AVM obliteration, MRI has been shown to have comparable accuracy.1
We evaluated clinical status before and after treatment, and at the time of final follow-up using the mRS scoring system.
Analysis
We performed analysis with SPSS Statistics version 17.0. A p value less than 0.05 indicated a statistically significant hazard ratio.
Results
Radiological result of target embolization
Table 2 shows the radiological result of target embolization. Targeted embolization decreased AVM volume and prepared the nidus for GKS treatment. Most of the hemorrhage risk factors (intranidus aneurysm, hemodynamic aneurysm and intranidus fistula) were target embolized. AVM-related aneurysms located in important arteries or with high embolization risks were untreated.
Table 2.
Characteristics and result of embolization.
| Embolization Characteristics | Value (%) |
|---|---|
| Max diameter prior embolization (cm) | |
| Average | 4.14 |
| Range | 1.5-12 |
| Max diameter after embolization (cm) | |
| Average | 3.18 |
| Range | 1.25-6.37 |
| Volume prior embolization (cm3) | |
| Average | 24.24 |
| Range | 0.75-115.38 |
| Volume after embolization (cm3) | |
| Average | 9.95 |
| Range | 0.59-57.8 |
| SM grade prior embolization | |
| Average | 3.06 |
| Range | 1-5 |
| SM grade after embolization | |
| Average | 2.71 |
| Range | 1-4 |
| No. of total embolizations | |
| 1 | 67(77.9) |
| 2 | 10(11.6) |
| 3 | 6(7.0) |
| 4 | 3(3.5) |
| Onyx volume (cm3) | |
| Mean | 2.2 |
| Median | 1.8 |
| Range | 0.2-10 |
| AVM decrease in size after embolization | |
| <50% | 43 (50) |
| 50-90% | 40 (46.5) |
| >90% | 3 (3.5) |
| AVM shape after embolization | |
| Compact | 68(79.1) |
| Pieces | 18(20.9) |
| Draining vein stenosis | |
| Stenosis prior embolization | 4 |
| Stenosis after embolization | 3 |
| Coexisting intranidus aneurysms | 29(33.7) |
| Target embolization | 24 |
| None target embolizaiton | 5 |
| Coexisting hemodynamic aneurysms | 5(5.8) |
| Target embolization | 4 |
| None target embolization | 1 |
| Coexisting fistula | 9 (10.5) |
| Target embolization | 8 |
| Partial embolization | 1 |
Embolization-related complications
Embolization-related complications were defined as complications caused by embolization or that occurred after embolization before GKS treatment. Sixteen patients (18.6%) had embolization-related complications, however, only one patient had permanent neurologic deficit at follow-up (Table 3). Six patients hemorrhaged after embolization. Four of them were AVM-related aneurysm rupture and two of them were draining vein stenosis.
Table 3.
Post embolization complications.
| Complications | Value (%) |
|---|---|
| Transient | |
| Hemorrhage | 6 (7.0) |
| Hemiparesis | 3 (3.5) |
| Defect of visual field | 1 (1.2) |
| Abducens nerve palsy | 1 (1.2) |
| Temporary apnoea | 1 (1.2) |
| Transient diplopia | 1 (1.2) |
| Permanent | |
| Thromboembolic complication | 1 (1.2) |
| Microcatheter entrapment | 2 (2.3) |
Obliteration rate of combined treatment
Of all the 86 combined treated patients, 60 patients (70%) were radiologically followed up by DSA and MRI. Of them, 44 patients were radiologically followed up for more than two years or proved total obliteration by imaging in two years. Twenty-one were followed up by DSA and 23 by MRI. Two patients with no radiological follow-up but who died of AVM hemorrhage were counted as unhealed. Forty-six (53.5%) patients were involved in calculation of the obliteration rate.
The obliteration rate calculated according to AVM diameters is shown in Table 4. Thirteen patients were totally obliterated and the obliteration rate was 28.2%. For ruptured AVMs, the obliteration rate was 38.9% and 21.4% for unruptured AVMs. The obliteration rate of ruptured AVMs was higher than that for unruptured lesions. The obliteration rate of AVMs with diameters no more than 3 cm was higher than that of larger 3 cm.
Table 4.
AVM obliteration rate at follow-up (%).
| Total | Max diameter prior embolization |
Max diameter prior GKS |
|||
|---|---|---|---|---|---|
| ≤3 cm | >3 cm | ≤3 cm | >3 cm | ||
| Total | 28.2 | 50.0 | 20.6 | 41.2 | 20.7 |
| Ruptured | 38.9 | 72.5 | 20.0 | 72.5 | 20.0 |
| Unruptured | 21.4 | 25.0 | 20.8 | 22.2 | 21.1 |
Clinical status follow-up after combined treatment
The clinical status improvement is shown in Table 5. Of all the 28 patients with the symptom of seizure, 11 of them showed significantly reduced seizure frequency after GKS treatment and 14 of them were completely seizure-free.
Table 5.
Outcome of Clinical Follow-up after GKS.
| Follow-up Characteristics | Value (%) |
|---|---|
| Follow-up duration (mths) | |
| Mean | 57.6 |
| Median | 57.6 |
| Range | 12.3-108.9 |
| Clinical status post GKS | |
| Improved | 42 (48.8) |
| Stable | 29 (33.7) |
| Hemorrhage | 9(10.6) |
| Headache | 3(3.5) |
| Seizure deterioration | 3 (17.4) |
| Seizure symptom | |
| Decreased frequency | 11 (39.3) |
| Seizure-free | 14 (50.0) |
| Increased frequency | 3 (10.7) |
| mRS scoring at diagnosis | |
| 0 | 70 (81.4) |
| 1 | 10 (11.6) |
| 2 | 4 (4.7) |
| 3 | 1 (1.2) |
| 4 | 1 (1.2) |
| mRS scoring at follow-up | |
| 0 | 78 (90.7) |
| 1 | 4 (4.7) |
| 2 | 1 (1.2) |
| 6 | 3 (3.5) |
The annual hemorrhage rate and mortality rate
The annual hemorrhage rate was 1.66% (9 hemorrhages/542.1 risk-years) for all the AVMs, 2.26% (6 hemorrhages/265.5 risk-years) for ruptured AVMs and 1.08% (3 hemorrhages/208.3 risk-years) for unruptured AVMs. Three patients died after combined treatment. The mortality rate was 3.5% and the annual mortality rate was 0.7%.
Nine AVMs occurred with hemorrhage during follow-up. Three of them were caused by draining vein stenosis, two were caused by intranidus aneurysm rupture, one combined with fistula, one combined with venous aneurysm and two were caused by residual AVM rupture.
Role of target embolization hemorrhage factors on hemorrhage complication
AVMs with hemorrhage risk factors (intranidus aneurysm, hemodynamic aneurysm and fistula) were separated into two groups. In the targeted embolization group, the risk factors were embolized. In the non-targeted embolization group, only the AVM nidus was embolized with hemorrhage risk factors left untreated. Chi square results showed the hemorrhage complications in the targeted embolization group were significantly lower than those in the non-targeted embolization group (p < 0.01). (Table 6)
Table 6.
Effect of target embolization on hemorrhage complication.
| Group | Hemorrhage | Stable | Total | P |
|---|---|---|---|---|
| Target embolization | 4 | 28 | 32 | 0.000 |
| Non-target embolization | 6 | 1 | 7 | (Fisher) |
| Total | 10 | 29 |
Discussion
Arteriovenous malformations (AVMs) are relatively rare cerebral lesions that may cause significant neurological morbidity in young people. The treatment of cerebral AVMs requires a multidisciplinary approach that includes microsurgery, endovascular embolization, and stereotactic radiosurgery (SRS). The first case of AVM embolization was described by Luessenhop and Spence in 1960 by indiscriminately injecting silicone microspheres directly into the carotid artery.2 With the advancement of new materials, endovascular embolization became an important method for the treatment of AVM. Symptoms of vascular steal phenomenon, venous hypertension, and seizures may obtain some benefit from endovascular embolization.3–6 A combination of embolization and radiosurgery is used in the treatment of brain AVMs as a routine strategy for large and complex AVMs when microsurgery is considered too risky and may render an originally untreatable AVM a potentially curable lesion.7–9 In most studies dedicated to the combination therapy of embolization followed by radiosurgery for the treatment of brain AVMs, particles or glue were used as the embolization agent. Onyx is a precipitating agent and allows for longer injection times. This makes it possible to achieve better occlusion of the nidus in one injection. The use of Onyx is associated with an increasing number of AVMs cured by embolization alone.
In this study, we used Onyx as an embolization agent to target embolize AVMs further treated by GKS for any residual nidus. In our series, the total annual hemorrhage rate was 1.66% for all AVMs after combined treatment, 1.08% for unruptured and 2.26% for ruptured AVMs. The annual hemorrhage rate in our series was lower than most reported annual hemorrhage risks of AVM which was about 1.3%--4% for unruptured AVMs and 6%--7% for ruptured AVMs.10,11 A recent meta-analysis of the natural history of AVM showed the overall annual hemorrhage rate was 3.0% with 2.2% for unruptured AVMs and 4.5% for ruptured AVMs.12 In a group of 168 patients with untreated unruptured AVMs Brown et al.13 reported an annual hemorrhage rate of 2.2%. Ding et al.14 reported the post-radiosurgery annual hemorrhage rate for patients with unruptured AVM was 1.6%.
The rate of total obliteration in our data is 28.2%, which is lower than rates in reported studies.15–17 One important reason is the median volume (14.1 cm3) in our data is significantly larger than most reported studies.15–17 To decrease the nidus volume most suitable for GKS by Onyx embolization was difficult. However, we adopt the idea of “targeted embolization” during our endovascular procedure. The role of target embolization is not to eliminate the nidus in one procedure, but to eliminate the aneurysms and fistula with high hemorrhage risk when left untreated.
Targeted embolization for decreasing AVM volume
The primary role for embolization was to decrease AVM volume till obliteration. Targeted embolization also has this goal and embolizes important feeding arteries, making any residual nidus more convenient for radiosurgery. Smaller nidus volume allows for higher radiation dosage and could increase the obliteration rate with fewer radiation complications. In our data, the average volume was 23.8 cm3 before embolization and decreased to 9.95 cm3 before GKS by Onyx embolization.
However, although we should decrease the AVM volume as much as we can when it adds no complication rate, there are some important principles we should obey during targeted embolization. Larger residual nidus volume, higher SM grade and residual nidus shape will lead to a low margin dose during radiosurgery treatment that will cause GKS treatment to fail. In addition, the obliteration rate was lower for deeply located AVM compared with cortical AVM. Therefore, during targeted embolization, we should try to eliminate the deeper part of the nidus and try to make the residual nidus compact after embolization. That will be easy for setting the GKS plan and using a higher radiation dose. Targeted embolization for decreasing AVM volume is the basis of GKS treatment. We should not blindly embolize the nidus only to decrease nidus volume.
Targeted embolization for eliminating AVM-related aneurysms
Associated cerebral aneurysms could be demonstrated in about 15% of all AVMs. However, on the basis of findings of superselective AVM microcatheterization, Turjman et al. reported an incidence of 58% of associated aneurysms.18 In this scenario, the annual bleeding rate may rise to 7%. If the aneurysm is intranidal, this risk may escalate to 9.8%.19–21 Therefore, the recommended therapeutic strategy is to obliterate the associated aneurysm first or simultaneously because of the lower annual bleeding rate of an AVM compared with an aneurysm and because the morbimortality of an aneurysm rupture is higher than that of an AVM.19,22,23 Obviously, this task is more feasible when the aneurysm is close to the nidus, so both AVM and aneurysm could be embolized. However, this is not always possible and different approaches may be necessary, increasing the complexity and risk of the overall treatment. Besides surgery, coil embolization also plays an important role in the treatment of a proximal aneurysms associated with an AVM.24
The rate of spontaneous regression of untreated feeding “pedicle aneurysms” after GKS for AVMs is about 50% and these aneurysms were mainly located on the distal portion of the feeder to the nidus.25 Redekop et al.21 reported on the effect of AVM treatment on aneurysms and they estimated the spontaneous regression rate of feeding artery aneurysms located between the proximal and distal pedicle artery. They revealed that the associated aneurysms on the distal pedicle feeder are easier to regress than those on the proximal pedicle feeder. This result suggests that associated aneurysms are more susceptible to regression in response to decreased blood flow into the nidus by the radiosurgical effect if a distal branch of the artery harbors the associated aneurysm. Overall, the fate of aneurysms in the setting of partially or completely obliterated AVMs remains unpredictable, and regression, enlargement, and de novo aneurysm formation after substantial AVM therapy have been reported, demanding close follow-up and treatment in case of enlargement.21,26–28 Valavanis and Yasargil and subsequent authors have suggested that appropriately targeted AVM embolization in otherwise untreatable AVMs may actually reduce the risk of hemorrhage, particularly if nidal aneurysms are embolized.29,30 In our data, aneurysm rupture was the main reason for a hemorrhage complication.
The most important principle for targeted embolization was aiming for AVM-related aneurysms (intranidus and hemodynamic). The statistical analysis showed significantly lower hemorrhage complications for residual nidus after elimination of hemorrhage risk factors (P < 0.01).
Targeted embolization for eliminating AVM-related fistula
Besides aneurysms, intranidal fistulas are critical angioarchitectural elements considered resistant to radiosurgery that need to be obliterated before radiosurgery to improve the radiosurgical outcome.31 Soderman et al.32 described intranidal fistulas as a “weak spot” for hemorrhage. That was a target we chose in patients in whom an intranidal aneurysm was not seen or could be targeted. These findings are in keeping with those of Crawford et al. who showed that partial targeted embolization with n-BCA reduced the long-term risk of hemorrhage by 24–78% when intranidal aneurysms or fistulas were targeted.33
In our data, eight out of nine AVM-related fistulas were target embolized. One fistula without targeted embolization hemorrhaged after embolization. Targeted embolization of AVM-related high-flow fistulas could decrease draining vein pressure and dilation. This could decrease AVM nidus pressure and reduce the hemorrhage risk.
In summary, target embolization of AVM combined with GKS for any residual nidus decreased the annual hemorrhage rate and improved clinical outcome with a low rate of permanent complications. However, the total obliteration rate was low in our group. We need to study retrospectively further follow-up data from the GKS center to establish whether pre-GKS embolization lowered the obliteration rate of AVM.
Our data do not contradict recent research such as the ARUBA study.34 The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain AVMs followed up for 33 months. However, the trial has selection bias and needs additional follow-up. Recently, another study compared the long-term outcomes of conservative management vs. intervention for unruptured cerebral AVMs.35 Among patients aged 16 years or older diagnosed as having unruptured cerebral AVM, use of conservative management compared with intervention was associated with better clinical outcomes for up to 12 years. However, longer follow-up is also required to understand whether this association persists. There was no sub-group for AVM-related aneurysms and fistulas. With development of new endovascular treatment material and improved embolization strategies, we believe endovascular embolization will further show its advantage in AVM treatment.
Funding
This work was supported by the Capital Medical Development Research Foundation (2009-2067).
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
We would like to thank Dr. Liu Ali and Pan Jian of Gamma Knife Center in Tiantan hospital (China) for providing GKS treatment and follow-up information.
References
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