Long-term outcomes of Spetzler-Martin grade IV and V arteriovenous malformations: a single-center experience

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  • 1 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing;
  • | 2 Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing;
  • | 3 Department of Neurosurgery, Peking University International Hospital, Peking University, Beijing;
  • | 4 China National Clinical Research Center for Neurological Diseases, Beijing; and
  • | 5 Beijing Translational Engineering Center for 3D Printer in Clinical Neuroscience, Beijing, China
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OBJECTIVE

This study aimed to explore whether intervention can benefit Spetzler-Martin (SM) grade IV–V arteriovenous malformations (AVMs).

METHODS

Eighty-two patients with SM grade IV–V AVMs were retrospectively reviewed from 2015 to 2018. Patients were divided into two groups: those who received conservative management (22 cases [26.8%]) and intervention (60 cases [73.2%], including 21 cases of microsurgery, 19 embolization, and 20 hybrid surgery). Neurofunctional outcomes were assessed with the modified Rankin Scale (mRS). The primary outcome was long-term neurofunctional status, and the secondary outcomes were short-term neurofunctional status, long-term obliteration rate, seizure control, and risk of subsequent hemorrhage.

RESULTS

Regarding the primary outcome, after an average of 4.7 years of clinical follow-up, long-term neurofunctional outcomes were similar after conservative management or intervention (absolute difference −0.4 [95% CI −1.5 to 0.7], OR 0.709 [95% CI 0.461–1.090], p = 0.106), whereas intervention had an advantage over conservative management for avoidance of severe disability (defined as mRS score > 3) (1.7% vs 18.2%, absolute difference 16.5% [95% CI −23.6% to 56.6%], OR 0.076 [95% CI 0.008–0.727], p = 0.025). Regarding the secondary outcomes, intervention was conducive to better seizure control (Engel class I–II) (70.0% vs 0.0%, absolute difference 70.0% [95% CI 8.6%–131.4%], p = 0.010) and avoidance of subsequent hemorrhage (1.4% vs 6.0%, absolute difference 4.6% [95% CI −0.4% to 9.6%], p = 0.030). In the subgroup analysis based on different intervention modalities, microsurgery and hybrid surgery achieved higher complete obliteration rates than embolization (p < 0.001), and hybrid surgery resulted in significantly less intraoperative blood loss than microsurgery (p = 0.041).

CONCLUSIONS

Intervention is reasonable for properly indicated SM grade IV–V AVMs because it provides satisfactory seizure control with decreased risks of severe disability and subsequent hemorrhage than conservative management.

Clinical trial registration no.: NCT04572568 (ClinicalTrials.gov)

ABBREVIATIONS

AVM = arteriovenous malformation; DSA = digital subtraction angiography; MRI = magnetic resonance imaging; mRS = modified Rankin Scale; SM = Spetzler-Martin; SRS = stereotactic radiosurgery.

OBJECTIVE

This study aimed to explore whether intervention can benefit Spetzler-Martin (SM) grade IV–V arteriovenous malformations (AVMs).

METHODS

Eighty-two patients with SM grade IV–V AVMs were retrospectively reviewed from 2015 to 2018. Patients were divided into two groups: those who received conservative management (22 cases [26.8%]) and intervention (60 cases [73.2%], including 21 cases of microsurgery, 19 embolization, and 20 hybrid surgery). Neurofunctional outcomes were assessed with the modified Rankin Scale (mRS). The primary outcome was long-term neurofunctional status, and the secondary outcomes were short-term neurofunctional status, long-term obliteration rate, seizure control, and risk of subsequent hemorrhage.

RESULTS

Regarding the primary outcome, after an average of 4.7 years of clinical follow-up, long-term neurofunctional outcomes were similar after conservative management or intervention (absolute difference −0.4 [95% CI −1.5 to 0.7], OR 0.709 [95% CI 0.461–1.090], p = 0.106), whereas intervention had an advantage over conservative management for avoidance of severe disability (defined as mRS score > 3) (1.7% vs 18.2%, absolute difference 16.5% [95% CI −23.6% to 56.6%], OR 0.076 [95% CI 0.008–0.727], p = 0.025). Regarding the secondary outcomes, intervention was conducive to better seizure control (Engel class I–II) (70.0% vs 0.0%, absolute difference 70.0% [95% CI 8.6%–131.4%], p = 0.010) and avoidance of subsequent hemorrhage (1.4% vs 6.0%, absolute difference 4.6% [95% CI −0.4% to 9.6%], p = 0.030). In the subgroup analysis based on different intervention modalities, microsurgery and hybrid surgery achieved higher complete obliteration rates than embolization (p < 0.001), and hybrid surgery resulted in significantly less intraoperative blood loss than microsurgery (p = 0.041).

CONCLUSIONS

Intervention is reasonable for properly indicated SM grade IV–V AVMs because it provides satisfactory seizure control with decreased risks of severe disability and subsequent hemorrhage than conservative management.

Clinical trial registration no.: NCT04572568 (ClinicalTrials.gov)

Arteriovenous malformations (AVMs) are caused by a direct connection between arteries and veins without an intervening capillary bed. Brain AVMs usually manifest as intracranial hemorrhage (30%–70% of cases), seizure (10%–30%), headache, or incidental findings (0%–15%).1 The primary purpose of treatment is to avoid neurological impairment due to future hemorrhagic stroke.2 The Spetzler-Martin (SM) grading system is widely used to estimate surgical risk.3 SM grade IV–V AVMs are classified as high-grade AVMs according to the Spetzler-Ponce classification.4 Due to the high surgical risk and high risk of poor postoperative neurological prognosis, observation is generally recommended for high-grade AVMs unless they rupture or lead to progressive neurological deficits.5

However, AVMs with an annual rupture risk of 1%–3% per year have been reported, and the lifetime cumulative rupture risk will reach an inevitable level if patients remain on conservative treatment.6 In addition, high-grade AVMs are more likely to incorporate high-flow and low-resistance hemodynamic features, and they are more likely to involve critical eloquent areas that may lead to severe and fatal neurological impairment if intracranial hemorrhage occurs.

Some studies proposed that the mortality rate after intervention for specified high-grade unruptured AVMs is acceptable.7,8 The purpose of our study was to clarify the long-term neurofunctional outcomes, obliteration rate, seizure control, and rupture risk of high-grade AVMs after different treatment modalities.

Methods

Study Design and Participants

The participants included in this study were prospectively registered in a multicenter research database of AVMs (MATCH study) from November 2015 to February 2018. This study was registered with the ClinicalTrials.gov database (http://clinicaltrials.gov), and its registration no. is NCT04572568. The study was carried out according to the guidelines of the Declaration of Helsinki and was approved by the institutional ethics committee. The inclusion criteria were as follows: 1) patients were diagnosed with AVM by digital subtraction angiography (DSA) or magnetic resonance imaging (MRI); 2) SM grade was IV or V; and 3) patients received follow-up for more than 3 years. The exclusion criteria were as follows: 1) concomitant diagnosis of hereditary hemorrhagic telangiectasia, arteriovenous fistula, and cavernous malformation; 2) emergency hospitalization (to exclude temporary neurological deterioration caused by acute hemorrhage); and 3) missing critical baseline information. After rigorous review, a total of 82 AVMs were included in the study cohort.

Data Collection and Definition

Demographic, clinical, and imaging data were recorded. Two distinct groups of management strategies were predefined: the conservative management group and the intervention group. Hemorrhagic presentation was attributed to AVM rupture. Morphological characteristics, including AVM size, eloquent area, deep venous drainage, flow-related aneurysm, and diffuse nidus, were based on the terminology for cerebral brain AVMs provided by a joint committee led by the American Society of Interventional and Therapeutic Neuroradiology.9–11

The primary outcome was long-term neurofunctional status, and the secondary outcomes were short-term neurofunctional status, long-term obliteration, long-term seizure control, and subsequent rupture risk. The long-term neurofunctional outcomes were evaluated at the last clinical follow-up, and the short-term neurofunctional outcomes were evaluated 1 week after the operation for the intervention group or 1 week after the treatment decision for the conservative management group. Confirmatory DSA was recommended to patients with complete obliteration on follow-up MRI. Complete obliteration was defined as a lack of abnormal flow voids on MRI or absence of anomalous arteriovenous shunting on DSA. The risk of subsequent hemorrhage was quantified on the basis of the annualized rupture rates. Neurofunctional status was assessed with the modified Rankin Scale (mRS) (favorable outcome defined as mRS score ≤ 2, neurofunctional disability mRS > 2, and severe disability mRS > 3). Seizure prognosis was evaluated with the Engel seizure outcome classification scale system (favorable control defined as Engel class I–II).

Follow-up with clinical visit and telephone interview was performed at the first 3–6 months and annually after discharge. Imaging follow-up consisted of MRI that was routinely performed semiannually for the first 2 years after discharge and annually thereafter. The researchers who assessed neurological status were blinded to the treatment strategies.

Selection of Treatment Strategies

The treatment strategy was developed on the basis of clinical symptoms, postoperative neurological dysfunctional risks, and patient requirements. Intervention was recommended for patients with moderate surgical risk (except those with involvement of an essential eloquent area, such as the brainstem and anterior/posterior central gyrus, or a hemispherically large diffuse nidus, etc.), intractable progressive seizure, previous rupture history, or combined rupture risk factors (aneurysm, arteriovenous fistula, etc.).

Neurosurgeons and interventional neuroradiologists prospectively planned the surgical procedure (microsurgery, embolization, and hybrid surgery) for each AVM at the multidisciplinary vascular conference held every weekday. Those patients with a large nidus (> 3 cm), deep location, multisource blood supply, and involvement of critical eloquent areas were considered to have complex AVMs. After comprehensive analysis of the angioarchitectural and hemodynamic characteristics, some complex cases were recommended for hybrid strategy. Hybrid surgery is a new interventional strategy defined as single-stage combined embolization and microsurgical resection, in which embolization is performed first on the deep feeding artery, aneurysm, arteriovenous fistula, and meningeal arteries feeding the nidus and then immediately followed by single-stage resection.12 All microsurgical procedures were performed with intraoperative neuronavigation, ultrasonography, indocyanine fluorescence angiography, and continuous monitoring of electroencephalography and somatosensory evoked potential. For patients with simple angioarchitecture and patients who received only palliative treatment, embolization was recommended as a priority.

Statistical Analysis

The mean (interquartile range) was reported for continuous data with normal and nonnormal distributions. The proportions of patients with each categorical variable were also recorded. The 2-tailed t-test was used to compare continuous variables with a normal distribution, whereas the Mann-Whitney U-test (Wilcoxon rank-sum test) was applied to compare nonnormally distributed continuous variables. The Pearson chi-square test and the Fisher exact test were utilized to compare categorical variables as appropriate. The Poisson rate test was employed to compare the annualized subsequent rupture rates between any two treatment strategies. The threshold for statistical significance was set at p < 0.05. Statistical analysis was performed using SPSS version 25.0 (IBM Corp.).

Results

Baseline Characteristics

We included a total of 82 patients with SM grade IV–V AVMs from our specific prospective AVM database who were treated from November 2015 to February 2018; of these, 60 (73.2%) underwent intervention (Table 1). Sixty-seven patients (81.7%) were classified with SM grade IV AVM. There were no significant differences in clinical manifestation and admission mRS score between the conservative management and intervention groups. Other angioarchitecture features were similar between these two groups, such as AVM size, eloquent area, flow-related aneurysm, deep venous drainage, and diffuse nidus. The mean ± SD duration of clinical follow-up was 4.7 ± 0.8 years.

TABLE 1.

Baseline characteristics

CharacteristicAll Patients (n = 82)Conservative Management (n = 22)Intervention (n = 60)p Value
Age, yrs30.1 ± 15.925.4 ± 17.831.8 ± 15.00.104
Male sex49 (59.8)15 (68.2)34 (56.7)0.262
Clinical manifestation
 Hemorrhage54 (65.9)13 (59.1)41 (68.3)0.434
 Seizure14 (17.1)4 (18.2)10 (16.7)>0.999
 Other14 (17.1)5 (22.7)9 (15.0)0.622
Hypertension5 (6.1)1 (4.5)4 (6.7)>0.999
Admission mRS score1.5 ± 0.81.6 ± 0.71.5 ± 0.90.670
Left-sided AVM45 (54.9)10 (45.5)35 (58.3)0.299
AVM size, cm5.5 ± 1.65.9 ± 1.55.4 ± 1.70.169
Eloquence77 (93.9)22 (100)55 (91.7)0.381
Deep venous drainage57 (69.5)15 (68.2)42 (70.0)0.874
SM grade0.110
 IV67 (81.7)15 (68.2)52 (86.7)
 V15 (18.3)7 (31.8)8 (13.3)
Flow-related aneurysm26 (31.7)7 (31.8)19 (31.7)0.990
Diffuse nidus18 (22.0)5 (22.7)13 (21.7)>0.999
Treatment modality
 Resection21 (25.6)21 (35.0)
 Embolization only19 (23.2)19 (31.7)
 Hybrid surgery20 (24.4)20 (33.3)
Follow-up time, yrs4.7 ± 0.84.6 ± 0.64.7 ± 0.80.441

Values are shown as number (%) or mean ± SD unless otherwise indicated.

Primary Outcomes

There were no statistical differences between the conservative management and intervention groups in terms of follow-up mRS score (absolute difference −0.4 [95% CI −1.5 to 0.7], OR 0.709 [95% CI 0.461–1.090], p = 0.106), favorable outcome (mRS score ≤ 2) (p = 0.730), and neurofunctional disability (mRS > 2) (p = 0.730) (Table 2). However, the intervention group had a lower incidence of long-term severe disability (mRS > 3) than the conservative management group (absolute difference 16.5% [95% CI −23.6% to 56.6%], OR 0.076 [95% CI 0.008–0.727], p = 0.025). In patients with ruptured AVMs, intervention was associated with reduced incidence of long-term severe disability (mRS > 3) when compared with conservative management (absolute difference 20.7% [95% CI 4.4%–37.0%], OR 0.083 [95% CI 0.008–0.889], p = 0.040). However, there were no significant differences in terms of the neurofunctional prognostic parameters among the patients with unruptured AVMs.

TABLE 2.

Primary outcomes

OutcomeAll PatientsConservative ManagementInterventionAbsolute Difference (95% CI)*OR (95% CI)p Value
Long-term neurofunctional outcome
All patients822260
 Follow-up mRS score2.0 ± 1.52.1 ± 1.31.7 ± 1.0−0.4 (−1.5 to 0.7)0.709 (0.461 to 1.090)0.106
 Favorable outcomes (mRS ≤2)65 (79.3)18 (81.8)47 (78.3)−3.5% (−27.2% to 20.1%)0.803 (0.231 to 2.791)0.730
 Neurofunctional disability (mRS >2)17 (20.7)4 (18.2)13 (21.7)−3.5% (−27.2% to 20.1%)1.245 (0.358 to 4.324)0.730
 Severe disability (mRS >3)5 (6.1)4 (18.2)1 (1.7)16.5% (−23.6% to 56.6%)0.076 (0.008 to 0.727)0.025
 Worsened mRS score20 (24.4)8 (36.4)12 (20.0)16.4% (−5.9% to 39.7%)0.438 (0.149 to 1.281)0.132
 Death2 (2.4)1 (4.5)1 (1.7)2.9 (−59.2% to 65.1%)0.356 (0.021 to 5.949)0.472
Unruptured AVMs28919
 Follow-up mRS score1.5 ± 1.11.9 ± 1.61.4 ± 0.70.5 (−1.6 to 2.6)0.634 (0.282 to 1.426)0.237
 Favorable outcomes (mRS ≤2)25 (89.3)8 (88.9)17 (89.5)0.6% (−23.9% to 25.1%)1.062 (0.084 to 13.517)0.963
 Neurofunctional disability (mRS >2)3 (10.7)1 (11.1)2 (10.5)0.6% (−23.9% to 25.1%)0.941 (0.074 to 11.973)0.963
 Severe disability (mRS >3)1 (3.6)1 (11.1)0 (0.0)11.1% (−3.6% to 25.8%)>0.999
 Worsened mRS score5 (17.9)2 (22.2)3 (15.8)6.4% (−24.0% to 36.8%)0.656 (0.089 to 4.837)0.679
 Death1 (3.6)1 (11.1)0 (0.0)11.1% (−3.6% to 25.8%)>0.999
Ruptured AVMs541341
 Follow-up mRS score1.9 ± 1.12.2 ± 1.11.8 ± 1.10.4 (−1.8 to 2.6)0.702 (0.405 to 1.214)0.206
 Favorable outcomes (mRS ≤2)40 (74.1)10 (76.9)30 (73.2)−3.7% (−31.0% to 23.6%)0.818 (0.189 to 3.535)0.788
 Neurofunctional disability (mRS >2)14 (25.9)3 (23.1)11 (26.8)−3.7% (−31.0% to 23.6%)1.222 (0.283 to 5.281)0.788
 Severe disability (mRS >3)4 (7.4)3 (23.1)1 (2.4)20.7% (4.4% to 37.0%)0.083 (0.008 to 0.889)0.040
 Worsened mRS score15 (27.8)6 (46.2)9 (22.0)24.2% (−3.7% to 52.1%)0.328 (0.088 to 1.225)0.097
 Death1 (1.9)0 (0.0)1 (2.4)−2.4% (−10.8% to 6.0%)>0.999

Values are shown as number, number (%), or mean ± SD unless indicated otherwise.

Positive differences indicate that the intervention group scored better than the conservative management group.

Statistically significant (p < 0.05).

Long-term neurofunctional outcomes (mRS scores) between pretreatment and follow-up were similar among all patients with high-grade AVM (p = 0.112), as well as among those with unruptured high-grade AVM (p = 0.156) and those with ruptured high-grade AVMs (p = 0.303) (Fig. 1). In addition, the proportions with worsened, unchanged, and improved mRS scores between pretreatment and follow-up were similar among all patients with high-grade AVMs (p = 0.095), as well as among those with unruptured high-grade AVMs (p > 0.999) and those with ruptured high-grade AVMs (p = 0.118) (Fig. 2).

FIG. 1.
FIG. 1.

Comparison of mRS scores at pretreatment and follow-up.

FIG. 2.
FIG. 2.

Proportions of patients with worsened, unchanged, and improved mRS scores.

Secondary Outcomes

Short-term neurofunctional outcomes (short-term mRS scores) were similar between the conservative management and intervention groups (absolute difference 0.5 [95% CI −0.6 to 1.5], OR 1.591 [95% CI 0.932–2.716], p = 0.208). However, the intervention group had decreased incidence of short-term favorable outcomes (mRS ≤ 2) (p = 0.042) and increased incidence of short-term disability (mRS > 2) than the conservative management group (p = 0.042) (Table 3). In addition, intervention was associated with increased satisfactory obliteration rate (absolute difference 68.3%, 95% CI 43.9%–92.7%, p < 0.001) and seizure control rate (Engel class I–II) (absolute difference 70.0%, 95% CI 8.6%–131.4%, p = 0.010) in comparison with conservative management. In terms of subsequent rupture risk, the Poisson rate test suggested that the conservative group had a significant higher annualized rupture risk (6.0% vs 1.4%; absolute difference 4.6% [95% CI −0.4% to 9.6%], p = 0.030).

TABLE 3.

Secondary outcomes

OutcomeAll Patients (n = 82)Conservative Management (n = 22)Intervention (n = 60)Absolute Difference (95% CI)*OR (95% CI)p Value
Short-term neurofunctional outcome
 Short-term mRS score1 (1 to 3)1 (1 to 2)1.5 (1 to 3)0.5 (−0.6 to 1.5)1.591 (0.932 to 2.716)0.208
 Favorable outcomes (mRS ≤2)60 (73.2)20 (90.9)40 (66.7)−24.2% (−45.8% to 2.6%)5.000 (1.062 to 23.545)0.042
 Neurofunctional disability (mRS >2)22 (26.8)2 (9.1)20 (33.3)−24.2% (−45.8% to 2.6%)5.000 (1.062 to 23.545)0.042
 Death0 (0.0)0 (0.0)0 (0.0)>0.999
Long-term complete obliteration41 (50.0)0 (0.0)41 (68.3)68.3% (43.9% to 92.7%)<0.001
Long-term seizure control
 Favorable control (Engel class I–II)7 (50.0) (n = 14)0 (0.0) (n = 4)7 (70.0) (n = 10)70.0% (8.6% to 131.4%)0.010
 De novo seizure3 (3.7)2 (9.1)1 (1.7)7.4% (−1.8% to 16.6%)0.169 (0.023 to 1.273)0.356
Subsequent hemorrhage9 (11.0)5 (22.7)4 (6.7)16.0% (0.7% to 31.3%)0.243 (0.059 to 1.007)0.051
 Hemorrhage frequency1064
 Observational duration, patient-years383.1100.4282.7
 Annualized rupture risk2.66.01.44.6% (−0.4% to 9.6%)0.030

Values are shown as number, number (%), or mean (interquartile range) unless indicated otherwise.

Positive differences indicate that the intervention group scored better than the conservative group.

Statistically significant (p < 0.05).

The Poisson rate test was used to compare annual rupture rates between groups.

Subgroup Analysis of the Intervention Group

Of the 60 AVM patients who opted for intervention, 21 (35.0%) received microsurgical resection, 19 (31.7%) had embolization, and 20 (33.3%) had single-stage combined embolization and resection (Table 4). In the comparison of the primary and secondary outcomes, no significant differences were found between the types of interventions in terms of long-term neurofunctional outcome (p = 0.695), short-term neurofunctional outcome (p = 0.069), subsequent hemorrhage (p = 0.092), and long-term seizure control (p = 0.142). However, the long-term obliteration rate of the microsurgical resection group (95.2%) was significantly different (p < 0.001) from those of the embolization group (5.3%) and hybrid group (100%). Additionally, intraoperative blood loss of the hybrid group was lower than that of the microsurgery group (557.5 ± 313.4 ml vs 804.8 ± 414.8 ml, p = 0.041).

TABLE 4.

Subgroup analysis of the intervention group

ParameterMicrosurgery (n = 21)Embolization (n = 19)Hybrid Surgery (n = 20)p Value
Age, yrs28.1 ± 17.834.0 ± 13.833.8 ± 12.60.269
Male sex9 (42.9)11 (57.9)14 (70)0.213
Clinical manifestation
 Hemorrhage14 (66.7)14 (73.7)13 (65)0.827
 Seizure4 (19)3 (15.8)3 (15)0.935
 Other3 (14.3)2 (10.5)4 (20)0.706
Admission mRS score1.7 ± 1.11.6 ± 1.01.2 ± 0.50.198
AVM size, cm5.1 ± 2.05.4 ± 1.65.4 ± 1.40.416
Eloquence19 (90.5)19 (100)17 (85)0.116
Deep venous drainage17 (81)12 (63.2)13 (65)0.394
SM grade IV19 (90.5)16 (84.2)17 (85.0)0.807
Flow-related aneurysm3 (14.3)7 (36.8)9 (45.0)0.090
Diffuse nidus6 (28.6)4 (21.1)3 (15.0)0.569
Deep perforating arteries9 (42.9)9 (47.4)10 (50)0.898
Intraoperative blood loss, ml804.8 ± 424.8557.5 ± 313.40.041*
Follow-up time, yrs4.9 ± 1.04.6 ± 0.74.6 ± 0.70.448
Primary long-term neurological outcomes
 Follow-up mRS score1.7 ± 0.91.7 ± 1.21.5 ± 0.80.695
 Favorable outcomes (mRS ≤2)15 (71.4)16 (84.2)16 (80)0.606
 Long-term disability (mRS >2)6 (28.6)3 (15.8)4 (20)0.606
 Severe disability (mRS >3)0 (0.0)1 (5.3)0 (0.0)0.311
 Worsened mRS score3 (14.3)4 (21.1)5 (25)0.679
 Death0 (0.0)1 (5.3)0 (0.0)0.311
Secondary outcomes
 Short-term neurological outcomes
  Short-term mRS score2.4 ± 1.21.6 ± 1.02.0 ± 1.20.069
  Favorable outcomes (mRS ≤2)11 (52.4)15 (78.9)14 (70.0)0.190
  Disability (mRS >2)10 (47.6)4 (21.1)6 (30.0)0.190
 Long-term complete obliteration20 (95.2)1 (5.3)20 (100)<0.001*
  Favorable seizure control (Engel class I–II) (n = 10)3 (75.0) (n = 4)1 (33.3) (n = 3)3 (100.0) (n = 3)0.142
 Subsequent hemorrhage1 (4.8)3 (15.8)0 (0.0)0.092

Values are shown as number, number (%), or mean ± SD unless indicated otherwise.

Statistically significant (p < 0.05).

Discussion

In this study, long-term neurofunctional outcomes were similar after conservative management or intervention, whereas intervention had an advantage over conservative management for avoidance of severe disability. Additionally, intervention is conducive to better seizure control and avoidance of subsequent hemorrhage. In the subgroup analysis based on different intervention modalities, microsurgery and hybrid surgery achieved higher complete obliteration rates than embolization, and hybrid surgery had significantly reduced intraoperative blood loss than microsurgery.

Conservative Management Versus Intervention

At present, there is no unified consensus regarding the management of high-grade AVMs. Previous studies advocated conservative observation because their data showed that current intervention strategies offer a high probability of complications.13 The American Heart Association/American Stroke Association proposed a scientific statement that conservative management is the first-line therapeutic option for SM grade IV–V AVMs if the patient has no progressive neurological deficits or high risk of recurrent hemorrhage.5 In addition, two prospective studies—ARUBA (A Randomized Trial of Unruptured Brain AVMs) and SIVMS (the Scottish Audit of Intracranial Vascular Malformation Prospective AVM Cohort Study)—found that conservative management could achieve better clinical outcomes than intervention for patients with an unruptured AVM, regardless of SM grade.14,15

However, intracranial hemorrhage due to AVM rupture can be catastrophic and fatal.5 Patients with AVMs reportedly have an average 15% rate of persistent disability and 15% risk of death after rupture.16 The annualized rupture risk was 6%–13.9% for ruptured SM grade IV–V AVMs, and the recurrent rupture rate varied from 6% to 16% at the 1st year after rupture.17,18 The result of hemorrhage was permanent decline in function, with mRS > 1 in 88% of patients and mRS > 2 in 69%.7 Thus, treatment decisions require a rigorous assessment of the benefit-risk ratio of intervention or observation.

In this study, although short-term neurofunctional outcomes were worse after intervention than conservative management, the long-term neurofunctional outcomes were similar between these two groups. In addition, intervention was superior to conservative management in terms of better seizure control and avoidance of severe disability and subsequent hemorrhage, which means that intervention may have a better benefit-risk ratio than conservative management. However, we also found that the long-term mRS scores, proportions of patients with favorable outcomes and worsened mRS scores, and rates of death were similar between the conservative and intervention groups, which means that intervention was more likely to have had a marginal benefit than conservative management.

Different Intervention Strategies

Microsurgical resection may have the highest complete obliteration rate among embolization and stereotactic radiosurgery (SRS), especially for SM grade I–II AVMs.19 The risks of long-term disability for patients with SM grade I–II, III, and IV–V AVMs were < 3%, 17%, and 45%, respectively.7,19 In this study, 95.2% achieved complete obliteration and 28.6% experienced long-term disability after resection, and the prognosis for neurofunction was slightly better than reported in previous studies.

Embolization is commonly used as a palliative treatment strategy or as an adjunct therapy to reduce AVM volume and flow before resection or SRS for high-grade AVMs.20 However, it has been reported that > 25% volume embolization in a single session for high-grade AVMs may be associated with an increased risk of perioperative complications,21,22 and incomplete embolization may further destabilize AVMs and increase intracranial hemorrhage risk by inducing HIF-1a, VEGF, and MMP-9 overexpression.23,24 In the present study, 5.3% of patients achieved complete embolization and 15.8% experienced subsequent hemorrhage after embolization. The high incidence of perioperative complication and low obliteration rate may indicate that palliative embolization cannot achieve satisfactory outcomes for high-grade AVMs.

Most previous studies suggested a multimodality strategy for high-grade AVMs.12,21,25 Hybrid surgery is a multimodality strategy that combines endovascular and microsurgical techniques in a single session. Reduction of nidus volume and flow, occlusion of deep perforating feeders, and detection of residual lesions in less time were considered unique advantages of hybrid surgery.26 Chen et al. indicated that the hybrid strategy is effective for the treatment of SM grade III/IV/V AVMs, and they recommended moderate embolization to facilitate subsequent microsurgical resection.12 Excessive embolization may harden the nidus and make the deep boundary of the nidus difficult to separate.12,27 In this study, hybrid surgery achieved the highest obliteration rate (100%) and lowest amount of intraoperative blood loss.

Single-session SRS appears to have limited efficacy for obliterating high-grade AVMs, and the outcomes of volume-stage and dose-staged SRS appear to be comparable to those of single-session SRS.28 Some studies suggested that pre-SRS embolization could effectively decrease AVM target volume, ultimately enhancing treatment efficacy.29,30 However, pre-SRS embolization may cause division of the nidus into distinct compartments, finally inducing a negative impact on obliteration.31

Limitations

Several potential limitations of this study should be noted. First, this was a single-center retrospective study, and selection bias existed. The operative indications and treatment strategy selections may vary according to institutional philosophy and experience, which weakens the validity of this study’s conclusions. Second, many patients in this cohort presented with hemorrhage and hemorrhagic predictors, which caused a higher incidence of subsequent hemorrhage in the conservative management group than reported in the previous study. Additionally, due to the small sample size, we did not further analyze different types of the high-grade AVMs. Future studies with more cases are warranted to confirm our findings.

Conclusions

Long-term neurofunctional outcomes were similar after conservative management or intervention, whereas intervention was superior to conservative management in terms of achieving better seizure control and avoiding severe disability and subsequent hemorrhage in patients with properly indicated SM grade IV–V AVMs. When used as an intervention, hybrid surgery may be the most worthwhile strategy due to its high obliteration rate and low amount of intraoperative blood loss.

Acknowledgments

We thank the Cerebrovascular Surgery Study Project of Beijing Tiantan Hospital and the Neurosurgery Center of Perking University International Hospital. This work was supported by the Natural Science Foundation of China (grant nos. 81571110, 81271314, 81771234, 81500995, and 81801140), Bai Qian Wan Talent Plan (grant no. 2017A07), and Beijing Municipal Administration of Hospital Incubating Program (grant no. PX2016034).

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: N Li, Yan, Z Li, R Li, Han, Meng, Jin, Yang Zhao. Acquisition of data: R Li, Han, Meng, Jin, Yang Zhao. Analysis and interpretation of data: N Li, Yan, Z Li, Y Chen, Ma. Drafting the article: N Li, Yan, Z Li. Critically revising the article: Yuanli Zhao, N Li, Yan, Z Li, X Chen, Wang. Reviewed submitted version of manuscript: Yuanli Zhao, N Li, Yan, Z Li, X Chen, Wang. Approved the final version of the manuscript on behalf of all authors: Yuanli Zhao. Statistical analysis: Y Chen, Ma. Administrative/technical/material support: Yuanli Zhao, X Chen, Wang. Study supervision: Yuanli Zhao, X Chen, Wang.

References

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    • Crossref
    • PubMed
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  • 2

    Klopfenstein JD, Spetzler RF. Cerebral arteriovenous malformations: when is surgery indicated?. Acta Neurochir (Wien). 2005;147(7):693695.

  • 3

    Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476483.

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    Spetzler RF, Ponce FA. A 3-tier classification of cerebral arteriovenous malformations. J Neurosurg. 2011;114(3):842849.

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    Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48(8):e200e224.

    • Crossref
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    Chen CJ, Ding D, Derdeyn CP, et al. Brain arteriovenous malformations: a review of natural history, pathobiology, and interventions. Neurology. 2020;95(20):917927.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Bervini D, Morgan MK, Ritson EA, Heller G. Surgery for unruptured arteriovenous malformations of the brain is better than conservative management for selected cases: a prospective cohort study. J Neurosurg. 2014;121(4):878890.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Chen Y, Li R, Ma L, et al. Single-stage combined embolization and resection for Spetzler-Martin grade III/IV/V arteriovenous malformations: a single-center experience and literature review. Front Neurol. 2020;11:570198.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Kim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL. Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology. 2014;83(7):590597.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Stapf C, Mast H, Sciacca RR, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66(9):13501355.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Atkinson RP, Awad IA, Batjer HH, et al. Reporting terminology for brain arteriovenous malformation clinical and radiographic features for use in clinical trials. Stroke. 2001;32(6):14301442.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Chen Y, Li R, Ma L, et al. Single-stage combined embolization and resection for Spetzler-Martin grade III/IV/V arteriovenous malformations: a single-center experience and literature review. Front Neurol. 2020;11 570198.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Marciscano AE, Huang J, Tamargo RJ, et al. Long-term outcomes with planned multistage reduced dose repeat stereotactic radiosurgery for treatment of inoperable high-grade arteriovenous malformations: an observational retrospective cohort study. Neurosurgery. 2017;81(1):136146.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614621.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):16611669.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Steiger HJ, Fischer I, Rohn B, Turowski B, Etminan N, Hänggi D. Microsurgical resection of Spetzler-Martin grades 1 and 2 unruptured brain arteriovenous malformations results in lower long-term morbidity and loss of quality-adjusted life-years (QALY) than conservative management—results of a single group series. Acta Neurochir (Wien). 2015;157(8):12791287.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Gross BA, Du R. Rate of re-bleeding of arteriovenous malformations in the first year after rupture. J Clin Neurosci. 2012;19(8):10871088.

  • 18

    Han PP, Ponce FA, Spetzler RF. Intention-to-treat analysis of Spetzler-Martin grades IV and V arteriovenous malformations: natural history and treatment paradigm. J Neurosurg. 2003;98(1):37.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Potts MB, Lau D, Abla AA, Kim H, Young WL, Lawton MT. Current surgical results with low-grade brain arteriovenous malformations. J Neurosurg. 2015;122(4):912920.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Mathis JA, Barr JD, Horton JA, et al. The efficacy of particulate embolization combined with stereotactic radiosurgery for treatment of large arteriovenous malformations of the brain. AJNR Am J Neuroradiol. 1995;16(2):299306.

    • Search Google Scholar
    • Export Citation
  • 21

    Chang SD, Marcellus ML, Marks MP, Levy RP, Do HM, Steinberg GK. Multimodality treatment of giant intracranial arteriovenous malformations. Neurosurgery. 2003;53(1):113.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Saatci I, Geyik S, Yavuz K, Cekirge HS. Endovascular treatment of brain arteriovenous malformations with prolonged intranidal Onyx injection technique: long-term results in 350 consecutive patients with completed endovascular treatment course. J Neurosurg. 2011;115(1):7888.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Starke RM, Komotar RJ, Hwang BY, et al. Systemic expression of matrix metalloproteinase-9 in patients with cerebral arteriovenous malformations. Neurosurgery. 2010;66(2):343348.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Sure U, Battenberg E, Dempfle A, Tirakotai W, Bien S, Bertalanffy H. Hypoxia-inducible factor and vascular endothelial growth factor are expressed more frequently in embolized than in nonembolized cerebral arteriovenous malformations. Neurosurgery. 2004;55(3):663670.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Ren Z, Wang S, Xu K, et al. The working road map in a neurosurgical Hybrid Angio-Surgical suite—development and practice of a neurosurgical Hybrid Angio-Surgical suite. Chin Neurosurg J. 2018;4(1):7.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Natarajan SK, Ghodke B, Britz GW, Born DE, Sekhar LN. Multimodality treatment of brain arteriovenous malformations with microsurgery after embolization with Onyx: single-center experience and technical nuances. Neurosurgery. 2008;62(6):12131226.

    • Search Google Scholar
    • Export Citation
  • 27

    Kocer N, Kandemirli SG, Dashti R, et al. Single-stage planning for total cure of grade III-V brain arteriovenous malformations by embolization alone or in combination with microsurgical resection. Neuroradiology. 2019;61(2):195205.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Patibandla MR, Ding D, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade IV and V arteriovenous malformations: an international multicenter study. J Neurosurg. 2018;129(2):498507.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Back AG, Vollmer D, Zeck O, Shkedy C, Shedden PM. Retrospective analysis of unstaged and staged Gamma Knife surgery with and without preceding embolization for the treatment of arteriovenous malformations. J Neurosurg. 2008;109(suppl):5764.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Kano H, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations after embolization: a case-control study. J Neurosurg. 2012;117(2):265275.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Sun DQ, Carson KA, Raza SM, et al. The radiosurgical treatment of arteriovenous malformations: obliteration, morbidities, and performance status. Int J Radiat Oncol Biol Phys. 2011;80(2):354361.

    • Crossref
    • Search Google Scholar
    • Export Citation

Illustration from Agosti et al. (E5). Used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.

  • View in gallery

    Comparison of mRS scores at pretreatment and follow-up.

  • View in gallery

    Proportions of patients with worsened, unchanged, and improved mRS scores.

  • 1

    Al-Shahi R, Warlow C. A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain. 2001;124(Pt 10):19001926.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Klopfenstein JD, Spetzler RF. Cerebral arteriovenous malformations: when is surgery indicated?. Acta Neurochir (Wien). 2005;147(7):693695.

  • 3

    Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986;65(4):476483.

  • 4

    Spetzler RF, Ponce FA. A 3-tier classification of cerebral arteriovenous malformations. J Neurosurg. 2011;114(3):842849.

  • 5

    Derdeyn CP, Zipfel GJ, Albuquerque FC, et al. Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48(8):e200e224.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Chen CJ, Ding D, Derdeyn CP, et al. Brain arteriovenous malformations: a review of natural history, pathobiology, and interventions. Neurology. 2020;95(20):917927.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Bervini D, Morgan MK, Ritson EA, Heller G. Surgery for unruptured arteriovenous malformations of the brain is better than conservative management for selected cases: a prospective cohort study. J Neurosurg. 2014;121(4):878890.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Chen Y, Li R, Ma L, et al. Single-stage combined embolization and resection for Spetzler-Martin grade III/IV/V arteriovenous malformations: a single-center experience and literature review. Front Neurol. 2020;11:570198.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Kim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL. Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology. 2014;83(7):590597.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Stapf C, Mast H, Sciacca RR, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology. 2006;66(9):13501355.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Atkinson RP, Awad IA, Batjer HH, et al. Reporting terminology for brain arteriovenous malformation clinical and radiographic features for use in clinical trials. Stroke. 2001;32(6):14301442.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Chen Y, Li R, Ma L, et al. Single-stage combined embolization and resection for Spetzler-Martin grade III/IV/V arteriovenous malformations: a single-center experience and literature review. Front Neurol. 2020;11 570198.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Marciscano AE, Huang J, Tamargo RJ, et al. Long-term outcomes with planned multistage reduced dose repeat stereotactic radiosurgery for treatment of inoperable high-grade arteriovenous malformations: an observational retrospective cohort study. Neurosurgery. 2017;81(1):136146.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614621.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):16611669.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Steiger HJ, Fischer I, Rohn B, Turowski B, Etminan N, Hänggi D. Microsurgical resection of Spetzler-Martin grades 1 and 2 unruptured brain arteriovenous malformations results in lower long-term morbidity and loss of quality-adjusted life-years (QALY) than conservative management—results of a single group series. Acta Neurochir (Wien). 2015;157(8):12791287.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Gross BA, Du R. Rate of re-bleeding of arteriovenous malformations in the first year after rupture. J Clin Neurosci. 2012;19(8):10871088.

  • 18

    Han PP, Ponce FA, Spetzler RF. Intention-to-treat analysis of Spetzler-Martin grades IV and V arteriovenous malformations: natural history and treatment paradigm. J Neurosurg. 2003;98(1):37.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Potts MB, Lau D, Abla AA, Kim H, Young WL, Lawton MT. Current surgical results with low-grade brain arteriovenous malformations. J Neurosurg. 2015;122(4):912920.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Mathis JA, Barr JD, Horton JA, et al. The efficacy of particulate embolization combined with stereotactic radiosurgery for treatment of large arteriovenous malformations of the brain. AJNR Am J Neuroradiol. 1995;16(2):299306.

    • Search Google Scholar
    • Export Citation
  • 21

    Chang SD, Marcellus ML, Marks MP, Levy RP, Do HM, Steinberg GK. Multimodality treatment of giant intracranial arteriovenous malformations. Neurosurgery. 2003;53(1):113.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Saatci I, Geyik S, Yavuz K, Cekirge HS. Endovascular treatment of brain arteriovenous malformations with prolonged intranidal Onyx injection technique: long-term results in 350 consecutive patients with completed endovascular treatment course. J Neurosurg. 2011;115(1):7888.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Starke RM, Komotar RJ, Hwang BY, et al. Systemic expression of matrix metalloproteinase-9 in patients with cerebral arteriovenous malformations. Neurosurgery. 2010;66(2):343348.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Sure U, Battenberg E, Dempfle A, Tirakotai W, Bien S, Bertalanffy H. Hypoxia-inducible factor and vascular endothelial growth factor are expressed more frequently in embolized than in nonembolized cerebral arteriovenous malformations. Neurosurgery. 2004;55(3):663670.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Ren Z, Wang S, Xu K, et al. The working road map in a neurosurgical Hybrid Angio-Surgical suite—development and practice of a neurosurgical Hybrid Angio-Surgical suite. Chin Neurosurg J. 2018;4(1):7.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Natarajan SK, Ghodke B, Britz GW, Born DE, Sekhar LN. Multimodality treatment of brain arteriovenous malformations with microsurgery after embolization with Onyx: single-center experience and technical nuances. Neurosurgery. 2008;62(6):12131226.

    • Search Google Scholar
    • Export Citation
  • 27

    Kocer N, Kandemirli SG, Dashti R, et al. Single-stage planning for total cure of grade III-V brain arteriovenous malformations by embolization alone or in combination with microsurgical resection. Neuroradiology. 2019;61(2):195205.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Patibandla MR, Ding D, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade IV and V arteriovenous malformations: an international multicenter study. J Neurosurg. 2018;129(2):498507.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Back AG, Vollmer D, Zeck O, Shkedy C, Shedden PM. Retrospective analysis of unstaged and staged Gamma Knife surgery with and without preceding embolization for the treatment of arteriovenous malformations. J Neurosurg. 2008;109(suppl):5764.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30

    Kano H, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for arteriovenous malformations after embolization: a case-control study. J Neurosurg. 2012;117(2):265275.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Sun DQ, Carson KA, Raza SM, et al. The radiosurgical treatment of arteriovenous malformations: obliteration, morbidities, and performance status. Int J Radiat Oncol Biol Phys. 2011;80(2):354361.

    • Crossref
    • Search Google Scholar
    • Export Citation

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