Risk of Future Hemorrhage From Unruptured Brain Arteriovenous Malformations The Multicenter Arteriovenous Malformation Research Study (MARS)

Helen Kim, PhD1,2; Jeffrey Nelson, MS1; Charles E. McCulloch, PhD2 et al

2025년 10월6일

JAMA Neurol. Published online: October 6, 2025.

Doi: 10.1001/jamaneurol.2025.3581

Abstract

Importance  Annual rates of first intracranial hemorrhage (ICH) from unruptured brain arteriovenous malformations (AVMs) are often quoted as 2% to 4% in clinical practice. Precise estimates and risk factors are unavailable to inform treatment decisions.

Objectives  To provide estimates of rates and risk factors for first ICH in a large cohort study of unruptured brain AVMs.

Design, Setting, and Participants   The Multicenter Arteriovenous Malformation Research Study (MARS) included data from 9 cohorts, each contributing 100 or more unruptured brain AVMs. The study was conducted from 2017 to 2023 with retrospective and prospective data collection for existing cohorts and/or new recruitment. This was an international study (2 population-based and 7 referral-based cohorts) that included participants diagnosed with an unruptured brain AVM.

Exposure  Demographic, clinical, and angiographic characteristics.

Main Outcomes and Measures  The primary outcome was time to first ICH after diagnosis of unruptured brain AVM. Data were collected using standardized definitions; missing data were imputed. Cox regression analysis was performed, censoring at first brain AVM treatment, death, or last visit, and allowing baseline hazards to vary by cohort.

Results   A total of 3225 individuals were eligible for participation in this study. After 195 exclusions, 3030 participants (median [IQR] age, 38 [25-50] years; 1524 female [50.3%]) were included. Among 2989 participants with unruptured brain AVMs, 1333 (45%) presented with seizure. The median (IQR) maximal brain AVM diameter was 3.1 (2.2-4.4) cm, 248 of 2466 AVMs (10%) had exclusively deep venous drainage, 297 of 2690 (11%) were in supratentorial deep or cerebellar locations, and 457 of 2440 (19%) had associated arterial aneurysms. First ICH occurred in 159 participants over 11 339 person-years of follow-up for an ICH rate of 1.40 (95% CI, 1.20-1.64) per 100 person-years. Significant independent risk factors included (1) increasing age category at diagnosis (hazard ratio [HR], 0.87; 95% CI, 0.53-1.41 for those aged 20 to 39 years; HR, 1.23; 95% CI, 0.74-2.04 for those aged 40 to 59 years; and HR, 2.01; 95% CI, 1.14-3.57 for those aged 60 years vs younger than 20 years; P = .008), (2) presence of associated aneurysms (HR, 1.66; 95% CI, 1.06-2.59; P = .03), and (3) cerebellar or supratentorial deep location (HR, 1.87; 95% CI, 1.16-3.00; P = .01).

Conclusions and Relevance   The annual ICH rate from unruptured brain AVM was lower than that commonly cited in clinical practice. Increasing age, associated arterial aneurysms, and cerebellar or supratentorial deep brain AVM location were associated with risk of first ICH. These results may be used to counsel patients about the natural history of unruptured brain AVMs.

Key Points

Question    What are the rate and risk factors for first intracranial hemorrhage (ICH) in the untreated clinical course of people diagnosed with unruptured brain arteriovenous malformations (AVMs)?

Findings     In this multicenter cohort of 3030 people with unruptured brain AVMs, the rate of ICH was lower than estimates used in clinical practice. Significant risk factors were increasing age, associated arterial aneurysms, and cerebellar or supratentorial deep brain AVM location.

Meaning   Results from this study can be used to counsel patients about the natural history of unruptured brain AVMs.

Table 2. Univariable and Multivariable Cox Regression Analysis of Time to Hemorrhage After Diagnosis in the Untreated Course of 3030 Patients With Unruptured Brain Arteriovenous Malformation (AVM)

Figure 3.  Kaplan-Meier Survival Curves

요약

·         중요성 : 임상 진료에서 파열되지 않은 뇌동정맥기형(unruptured brain arteriovenous malformation, AVM)의 연간 최초 두개내출혈(intracranial hemorrhage, ICH) 발생률은 흔히 2%에서 4%로 인용된다. 그러나 치료 결정을 뒷받침할 정확한 발생률 추정치와 위험 인자에 대한 근거는 부족한 실정이다.

·         목적 : 대규모 코호트 연구를 통해 파열되지 않은 뇌 AVM에서 최초 ICH의 발생률과 위험 인자를 제시하고자 한다.

·         설계, 환경 및 대상자 : 다기관 동정맥기형 연구(Multicenter Arteriovenous Malformation Research Study, MARS)는 각각 100명 이상의 파열되지 않은 뇌 AVM 환자를 포함한 9개 코호트의 자료를 통합하였다. 본 연구는 2017년부터 2023년까지 수행되었으며, 기존 코호트에 대한 후향적 및 전향적 자료 수집과/또는 신규 대상자 모집을 포함하였다. 본 연구는 국제 다기관 연구로, 2개의 인구 기반 코호트와 7개의 의뢰 기반 코호트가 포함되었으며, 파열되지 않은 뇌 AVM으로 진단된 대상자를 포함하였다.

·         노출 변수: 인구학적, 임상적 및 혈관조영학적 특성

·         주요 결과 및 측정치: 주요 결과는 파열되지 않은 뇌 AVM 진단 이후 최초 ICH까지의 시간이었다. 자료는 표준화된 정의를 사용하여 수집되었으며, 결측치는 대치(imputation) 하였다. Cox 회귀분석을 시행하였고, 뇌 AVM에 대한 최초 치료, 사망 또는 마지막 추적 관찰 시점에서 검열하였으며, 코호트별로 기저 위험도(baseline hazard)가 달라질 수 있도록 허용하였다.

·         결과 : 총 3225명이 연구 참여 자격을 충족하였으며, 이 중 195명을 제외하고 3030명(중앙값 [사분위수 범위], 38세 [25–50세]; 여성 1524명 [50.3%])이 분석에 포함되었다.

파열되지 않은 뇌 AVM을 가진 2989명 중 1333명(45%)은 경련(seizure)으로 발현하였다. 뇌 AVM의 최대 직경 중앙값(IQR)은 3.1cm (2.2–4.4cm)였으며,  2466개 중 248개(10%)는 순수 심부 정맥 배액을 보였다.  690개 중 297개(11%)는 천막상부 심부 또는 소뇌 위치에 있었고,  2440개 중 457개(19%)에서는 연관된 동맥류가 관찰되었다. 총 11339 인년(person-years)의 추적 관찰 동안 159명에서 최초 ICH가 발생하였으며, ICH 발생률은 인년당 1.40건(95% CI, 1.20–1.64)이었다. 독립적으로 유의한 위험 인자는 다음과 같았다:

·         진단 시 연령 증가 (20–39세: HR 0.87, 95% CI 0.53–1.41; 40–59세: HR 1.23, 95% CI 0.74–2.04; 60세 이상: HR 2.01, 95% CI 1.14–3.57; 기준군 <20세; P = .008),

·         연관된 동맥류의 존재 (HR 1.66; 95% CI, 1.06–2.59; P = .03),

·         소뇌 또는 천막상부 심부 위치 (HR 1.87; 95% CI, 1.16–3.00; P = .01).

·         결론 및 의의 :

파열되지 않은 뇌 AVM의 연간 ICH 발생률은 임상에서 흔히 인용되는 수치보다 낮았다. 연령 증가, 연관된 동맥류, 그리고 소뇌 또는 천막상부 심부 위치는 최초 ICH 발생 위험과 관련이 있었다. 이러한 결과는 파열되지 않은 뇌 AVM의 자연 경과에 대해 환자를 상담하는 데 활용될 수 있다.