Brain arteriovenous malformation (AVM) is a rare congenital vascular malformation detected at an annual incidence rate of 1 per 100,000 person-years.1 The annual hemorrhage rates are approximately 2% to 4% for all brain AVMs, and 1% to 3% for unruptured AVMs.23 The natural history of unruptured AVMs is more benign than that of ruptured ones because of their low hemorrhage risk.1 Patients with ruptured AVMs require a definite treatment because their risk of recurrent hemorrhage is higher than the risk of initial hemorrhage in patients with unruptured AVMs.34 However, the management of unruptured AVMs is controversial. The current option for the management of brain AVMs include a microsurgical resection, endovascular embolization, and stereotactic radiosurgery (SRS), which can sometimes be used in a multidisciplinary approach. Although a complete AVM removal can achieve an immediate cure and prevent future hemorrhagic risk,56 it has a high treatment-related morbidity. Any intervention for unruptured AVM is prophylactic and is justified only when the risk of morbidity and mortality from the intervention is lesser than the risk from the AVM's natural course. A randomized trial of unruptured brain arteriovenous malformations (ARUBA) and the prospective Scottish Audit of Intracranial Vascular Malformations (SAIVM) are comparative AVM cohort studies, which reported that the patients with unruptured AVMs assigned to conservative management had superior outcomes compared to those assigned to an intervention.78 In the ARUBA study, the patients assigned to the medical arm received pharmacological therapy for the existing medical disorders, such as seizure and headaches, or any coexisting vascular risk factors, such as diabetes and arterial hypertension as needed.7 The patients allocated to the interventional arm received interventional therapy, including neurosurgical, endovascular, or radiotherapy, as was appropriate. However, these studies had numerous limitations and were subjected to criticism. Additionally, many studies have reported long-term outcomes after intervention for unruptured AVMs much better than those described in ARUBA study.910111213 The aim of this study was to investigate the efficacy of GKS in the treatment of brain AVMs through comparison of its outcome in ARUBA-eligible patients to the outcomes of the ARUBA study. Although similar studies have already been published in other countries, this study is significant for providing the first comparison to the ARUBA study in Republic of Korea where GKS has a predominant role in treatment of AVM.

AVMs present a significant risk of an intracerebral hemorrhage that may last for a lifetime, and lead to catastrophic morbidity. The primary goal of the AVM treatment is to eliminate any future risk of new or recurrent hemorrhage through total AVM nidus obliteration. Surgical resection of the AVM nidus has been considered as the primary treatment. However, many studies have reported permanent morbidity of 5% to 12%,212223 particularly in the case of surgical resection of unruptured AVMs.824 GKS has been widely accepted as an alternative treatment modality with high obliteration and low mortality rates, particularly for AVMs that are small in size and located in deep or eloquent brain areas. In this study, the post-GKS AVM obliteration rates based on MRI and DSA were 70.5% and 90.1% at 5 and 10 years, respectively, which is comparable to those documented in previous reports. However, GKS still poses a hemorrhagic risk during the latency period of 3–4 years.21 Several studies have reported a hemorrhage rate of 1.3%–5.0% during the latency period, and a reduction of annual hemorrhage rate after SRS.102526 Maruyama et al.25 analyzed the outcomes of AVM radiosurgery in a cohort of 500 patients. They reported that the annual hemorrhage rate was reduced from 8.4% to 5.0% during the latency period after the SRS. In particular, SRS significantly reduced the hemorrhagic risk to a greater extent in patients with ruptured AVMs compared to those with unruptured ones. Yen et al.27 demonstrated that the annual post-GKS hemorrhage rate was reduced from 6.6% to 2.5% during the latency period. The annual hemorrhage rate was reduced from 10.4% to 2.8%, and from 3.9% to 2.2% in patients with ruptured and unruptured AVMs, respectively. Further, the permanent morbidity after SRS was much lower than the surgical morbidity. In the present study, permanent morbidity after GKS was 3.0%, which was similar to the 2.1% to 5.7% reported by other studies.2628

The ARUBA, along with the SAIVM prospective AVM cohort study, questioned the benefit of a prophylactic intervention for unruptured AVMs. The ARUBA study, at a mean follow-up of 33 months, reported 3-fold higher rates of symptomatic stroke or death as well as significantly higher rates of hemorrhagic stroke in the patients with unruptured AVMs who underwent an intervention than those in the patients who were treated conservatively.7 The SAIVM prospective cohort study compared non-randomized cohorts with unruptured AVMs of treated versus untreated patients, with a median follow-up of 6.9 years.8 The sustained morbidity and death rates during the follow-up of first 4 years were significantly higher in the treated AVMs than in the untreated ones. Although there was no significant difference in the mortality rates between the treated and untreated patients after age adjustment, the death rates after a follow-up of 12 years were significantly higher in the untreated arm. Several criticisms have been raised on the aforementioned publications regarding the limitations of the trial, including the relatively short mean follow-up period, small sample size, patient selection bias, the considerable heterogeneity of the modalities used to treat AVMs in the interventional arm, and an unexpected excessive rate of AVM hemorrhage in the interventional arm.29303132 In this study, the outcomes of the ARUBA-eligible patients who underwent GKS with a mean follow-up of 4.6 years are comparable to those of the patients in the ARUBA study who were randomized in the medical arm, and were superior to those of the patients who were randomized in the interventional arm. The overall stroke or death rate of the ARUBA-eligible cohort was significantly lower than that the patients in the interventional arm of the ARUBA study (RR, 0.264; P < 0.001), but similar to that of the patients in its medial arm (14.0% vs. 10.1%, P = 0.601). Although the overall stroke or death rate of the ARUBA-eligible cohort did not significantly differ from that of the medical arm in the ARUBA study in a limited follow-up period, the long-term outcome is very likely to be better with GKS, considering the much lower risk of hemorrhage in once obliterated AVMs and the persistently constant risk of hemorrhage over the whole lifespan in untreated AVMs. Also, AVM obliteration was achieved in 62.1% of the ARUBA-eligible patients treated with GKS, compared to none in the medical arm of the ARUBA study. Furthermore, because more than half of the patients assigned to the interventional arm either had not completed or initiated therapy at the time of the initial interim analysis, the actuarial obliteration rate of the interventional arm of the ARUBA study can be assumed to be less than 50%. Therefore, GKS can be considered a safe and effective alternative treatment option for brain AVMs.

Although similar studies have already been published in other countries, and the treatment results in the present study were not different from those in other countries, this study has significance as the first outcome analysis based on domestic data. Currently utilization of radiosurgery for treatment of AVMs is much more prevalent than the other countries and more than 70% of the all patients diagnosed having AVMs are treated with radiosurgery in Korea (unpublished data). It means that majority of the patients with unruptured AVMs were treated with radiosurgery and selection bias in this study may not be serious though data was collected retrospectively. Therefore, a better outcome after GKS in this study compared to that of ARUBA is not caused by selection bias, which once again demonstrates that the reliability of the ARUBA data is low. Although the ARUBA study was published in a highly qualified academic journal by virtue of a formal structure of prospective randomized trial, it objectively overlooked not only the characteristics and natural course of disease but also other important factors affecting the therapeutic outcome. As a result, inappropriate conclusions were drawn based on impractical results. The ARUBA study may be a representative study that distorted the original meaning of the evidence-based medicine by making research design by tabletop logic and claiming the wrong results acquired by applying formal logic by force as evident, in a case where prospective randomized trial is not possible in reality.

This study has several limitations. First, there is the possibility of selection bias due to the absence of an untreated control group to compare the efficacy of GKS for brain AVMs within this study. Instead, the efficacy of GKS for brain AVMs was investigated by comparison with the medical and interventional arm of the ARUBA study. Second, there is a possibility of inherent selection bias because this study is a retrospective study. Third, this study may have a referral bias in clinical and epidemiological results due to the characteristics of a large tertiary medical center. Finally, a potentially serious bias or confounding caused by a direct comparison between retrospective and prospective studies cannot be ruled out. However, there is no alternative way to compare outcomes according to different treatment modalities. AVM is a rare disease that requires a long observation period for the clinician to be able to determine the final outcome, and it is difficult to recruit a homogenous patient group that is big enough for a prospective controlled study. Considering the highly invasive nature of the therapeutic procedure and the potential risk of fatal complications, randomization of treatment will not easily be accepted by patients. Furthermore, such a clinical trial may even be considered unethical, because the optimal choice of treatment modality is often intuitively obvious, in some subgroups of the patients, from the perspective of an experienced clinician. Therefore, a comparison between retrospective and prospective studies poses inevitable problems, but it is the only feasible method, in reality, to establish the guidelines that are necessary for the clinical practice.

The natural history of brain AVMs is still unclear in many aspects. Whether or not unruptured AVM should be treated remains the subject of a debate not reaching full consensus. In this study, GKS was shown to achieve a favorable outcome with low procedure-related morbidity in majority of the ARUBA-eligible patients. The outcome after GKS in our patients was not inferior to that of medical care alone in ARUBA study. It is suggested that GKS is rather superior to medical care considering the short follow-up duration of the ARUBA study. Considering lifelong risk of hemorrhage in untreated AVMs it is not justified to unconditionally withhold GKS for unruptured AVMs with only exception in the patients with short life expectancy.