24 Natural History and Management Options of Ruptured Brain Arteriovenous Malformation

Darius Tan, Helen Huang, and Leon T. Lai

Abstract

Ruptured bAVM have an increased risk of rerupture. Various other factors such as location, associated aneurysm, and drainage may also affect rerupture risk. Intervention options include surgery, stereotactic radiosurgery, endovascular embolization, or combinations of the above with the goals to obviate further rupture risk. Each of these modalities have associated benefits and risks that clinicians need to weigh carefully in decision making in order to provide the patient with the best available treatment. This chapter aims to review the current evidence in relation to the natural history and treatment options in ruptured brain arteriovenous malformations.

Ruptured brain arteriovenous malformations (bAVMs) are relatively uncommon with reported incidence between 0.4 and 3.5 per 100,000 person-years.1^{,​ 2,​ 3,​ 4,​ 5} Approximately 1.4% of strokes can be attributed to ruptured bAVM.⁶ In young patients (≤ 40 years), ruptured bAVM accounts for approximately 33% of intracerebral hemorrhages (ICHs)⁷ and represents a major cause of morbidity and mortality.^{8,​ 9,​ 10,​ 11,​ 12,​ 13} The prevalence of incidental bAVM is estimated to be approximately 45 per 100,000 persons.¹⁴ However, this may be an overestimate, and to date, there are no studies to determine an accurate prevalence of bAVMs.^{15,​ 16,​ 17} The mean age at presentation is around 33.7 years (95% confidence interval [CI]: 31.1–36.2), with no significant differences in gender predilection (females: 45%; 95% CI: 42–49%).¹³ The risk of rupture is cumulative over a lifetime, with the overall risk potentially affected by age; however, there has been suggestions that pediatric bAVM may have a greater propensity for rupture.^{18,​ 19,​ 20,​ 21}

Although there are individuals with a clear genetic predisposition, for example, hereditary hemorrhagic telangiectasia, most bAVMs are sporadic.²² Molecular association with bAVMs has been increasingly studied such as matrix metalloproteinases, ApoE ꞓ2, interleukin-1α, and interleukin-6.²³ These have been found to be in greater expression in individuals with ruptured bAVMs and observational studies have shown an increased risk of hemorrhage in the affected individuals.^{24,​ 25,​ 26,​ 27,​ 28,​ 29,​ 30,​ 31} Single nucleotide polymorphisms in proinflammatory molecules such as interleukin-1 lead to increased inflammation of vasculature that has been associated with increased bAVM rupture risk and may contribute to the natural history of bAVM rupture.²⁴

Understanding the natural clinical sequelae following bAVM rupture is important to guide clinical practice. Few studies in the literature have captured the natural history of ruptured bAVM due to selection bias, retrospective analysis, short follow-up, and/or partial or complete treatment. This chapter aims to summarize the natural history and treatment options for ruptured bAVMs.

24.2 Selected Papers on the Natural History of Ruptured bAVMs

●Stapf C, Mast H, Sciacca RR, et al. Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology 2006;66(9):1350–1355

●Yamada S, Takagi Y, Nozaki K, Kikuta K, Hashimoto N. Risk factors for subsequent hemorrhage in patients with cerebral arteriovenous malformations. J Neurosurg 2007;107(5):965–972

●Kim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL; MARS Coinvestigators. Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology 2014;83(7):590–597

●da Costa L, Wallace MC, Ter Brugge KG, O’Kelly C, Willinsky RA, Tymianski M. The natural history and predictive features of hemorrhage from brain arteriovenous malformations. Stroke 2009;40(1):100–105

24.3 Natural History of Ruptured bAVM

To date, there are no specific studies that examine the natural history of ruptured bAVM. Most literature data were discussed in conjunction with unruptured cases. Ruptured bAVMs may lead to variable clinical presentation depending on hemorrhage location, degree of raised intracranial pressure (ICP), and possible associated hydrocephalus from intraventricular hemorrhage. Typically, grading scales for subarachnoid hemorrhage have been used for clinical assessment following rupture. In addition, novel grading scales (Table 24.1 and Table 24.2) have been developed to correlate with outcomes.^{32,​ 33}

Table 24.1 Ruptured arteriovenous malformation grading scale³³

Table 24.2 Arteriovenous malformation–related intracerebral hemorrhage (AVICH) score³²

Compared to spontaneous/primary ICH, ruptured bAVM is generally associated with a more favorable clinical outcome.^{9,​ 35,​ 36} Younger patients (20–40 years) have a lower risk of death and are more likely to be discharged home.³⁶ However, outcomes are generally worse for ICH, when compared to subarachnoid hemorrhage or intraventricular hemorrhage.³⁵ Whereas studies have a heterogenous classification of morbidity, approximately 60% of patients with ruptured bAVMs will have a modified Rankin Scale (mRS) score of 1 to 2 at 1 year postrupture.⁹ Comparison of outcomes for ICH due to bAVM versus non-bAVM-related cases are summarized in Table 24.3.

Table 24.3 Comparison of outcomes for intracranial hemorrhage due to bAVM versus non-bAVM related

Morgan et al reported that for ruptured bAVMs that are untreated, subsequent hemorrhage has a cumulative 70% risk of new permanent neurological deficit or death and a 42% risk of death.10 Choi et al suggested recurrent AVM hemorrhage does not convey much additional mortality risk. Recurrent hemorrhage only resulted in a slightly greater morbidity than initial hemorrhage (mean National Institute of Health Stroke Scale [NIHSS]: 5.7 ± 8.4 compared to 3.6 ± 6.2).³⁷ This has also been shown in other smaller studies.^{38,​ 39} These studies are limited to retrospective, relatively small-sized studies, or databases with methodological limitations, which limits generalization of results and the quantification of effect. Nonetheless, it is accepted that the risk of recurrent hemorrhage following bAVM rupture is initially higher.³⁹

24.4 Risk of Recurrent Hemorrhage

Once a bAVM has ruptured, its behavior is altered and the risk of rehemorrhage increases. Rate of rerupture is between 6.2 and 15.4% in the first year,¹⁹ and gradually returning to the baseline in the following years. Key studies are summarized in Table 24.4 and Fig. 24.1 (as graphical representation). A meta-analysis including 16,978 patients-years calculated an annual rerupture rate of 4.5% (range: 3.7–5.5%) compared to 2.2% in unruptured bAVM (range: 1.7–2.7%) and the risk of hemorrhage following rupture of bAVM was HR 3.2 (95% CI 2.1–4.3) compared to unruptured bAVM.¹³ A recent review by Morgan et al demonstrated in survival curves for cumulative risk of rupture based on studies with substantial sample sizes and follow-up an estimated risk of rerupture of 4.8% in the first 8 years that subsequently decreased to 1.8% per year.¹⁰ In all studies, due to relatively short length of follow-up, it is difficult to predict rupture risk beyond 10 years.¹⁰

Table 24.4 Rehemorrhage rates following ruptured bAVM

24.5 Other Factors

A recent meta-analysis demonstrated prior hemorrhage to infer the greater risk for subsequent rupture (hazard ratio [HR]: 3.2; 95% CI: 2.1–4.1), followed by deep nidal location (HR: 2.4; 95% CI: 1.4–3.4), exclusively deep venous drainage (HR: 2.4; 95% CI: 1.1–3.8), and associated aneurysm (HR: 1.8; 95% CI: 1.6–2.0).¹³ Female gender, age, and size were shown to have no significant relationship to hemorrhage.¹³ Age was shown to be a significant factor for rupture in the Multicenter AVM Research Study (MARS), which was in concordance with Stapf et al.⁴³ However, multiple other studies have not confirmed this relationship.^{21,​ 40,​ 41,​ 42} It has been suggested that lack of treatment in the older population, or increased formation with age of associated AVM aneurysm may confound the results.¹⁰ Other factors that are thought to influence the rate of hemorrhage in ruptured bAVM include associated intranidal/perinidal aneurysms, location, deep venous drainage, pregnancy, and size. Importantly, these risk factors can change with hemorrhage, which may reflect alteration of physiology and flow dynamics of the bAVM following rupture.^{19,​ 43} Therefore, these risk factors are not static and need to be taken into consideration with other factors when discerning the natural history between an already ruptured bAVM compared to an unruptured bAVM (Table 24.5).

Table 24.5 Key factors associated with risk of rehemorrhage following ruptured bAVM

24.6 Associated Aneurysms

Associated aneurysms are found in approximately 20% of bAVMs and can be classified according to location and whether it is within the nidus, distant from the nidus, or flow related (saccular aneurysm from artery feeding the nidus).13^{,​ 44} Flow-related aneurysms can be further divided into whether they stem from a major proximal artery (i.e., internal carotid artery, circle of Willis, anterior cerebral artery up to the anterior communicating artery, vertebrobasilar trunk, and middle cerebral artery) or distal to the aforementioned. A large, pooled analysis of bAVM-associated aneurysms showed flow-related aneurysms account for approximately 71% (proximal 47%, distal 25%), intranidal aneurysm account for 25%, and unrelated aneurysms account for 4%.⁴⁴ In this study of 10,093 ruptured bAVMs (first and/or subsequent), the source of bleed was from the aneurysm in 49% of cases and the nidus in 45% of cases.⁴⁴ There are limited studies to adequately assess the natural history of subsequent rupture, but there may be a trend for increased bAVM rupture if there is an associated aneurysm.^{43,​ 45} One study showed associated aneurysms (either intranidal or feeding artery aneurysms) had an odds ratio of 2.27 (95% CI: 1.55–3.34; p  < 0.0001) of rupture at initial presentation, but this effect was not significant when analyzing those that already ruptured with an HR of 1.83 (95% CI: 0.95–3.5; p = 0.07).⁴³ In contrast, in a study of ruptured pediatric bAVMs, there was a relative risk of 2.68 (p = 0.04) of subsequent rupture with associated aneurysms.⁴⁵

24.7 Infratentorial Brain Arteriovenous Malformations

Few studies have explored the relation between infratentorial bAVM and rupture. Although it is thought that the initial risk of rupture from an infratentorial bAVM is higher than that of a supratentorial bAVM with odds of rupture up to 3.89 (95% CI: 1.10–13.72; p = 0.0092),41^{,​ 43,​ 46} this effect may be different with subsequent rupture. Stapf et al comprehensively studied risk factors at initial presentation, and then on subsequent hemorrhage, and found the risk profile altered.⁴³ For instance, infratentorial AVM location had an initial hemorrhage odds ratio of 3.27 (95% CI: 1.93–5.53; p  < 0.0001), whereas posthemorrhage, the HR of rupture was 0.68 (95% CI: 0.16–2.82; p = 0.59). These effect differences may have treatment bias due to small numbers or confounding factors. Small sample size in analyzing risk factors in the hemorrhagic group may also be due to treatment bias as infratentorial bAVMs may be treated more expediently due to poorer outcomes in infratentorial bAVMs,^{39,​ 47} whereas poor outcome in this group may reduce numbers for further analysis in the subsequent hemorrhage cohort. Therefore, these challenges must be kept in mind when interpreting the risk factors associated with subsequent bAVM rupture.

24.8 Deep Venous Drainage

Deep venous drainage is defined as venous drainage into deep veins that include the internal cerebral veins, basal veins, or precentral cerebral veins. Within the posterior fossa, drainage to locations other than the straight sinus, torcula, or transverse sinus is considered deep.⁴⁸ Drainage to the deep venous drainage is associated with increased risk of rupture (HR: 1.3; 95% CI: 0.9–1.75; p  > 0.05), and this risk is further increased with solely deep venous drainage (HR: 2.4; 95% CI: 1.1–3.8; p  < 0.05).^{13,​ 21,​ 43,​ 49} This has been postulated to be secondary to increased pressure in the deep venous system that translates to increased pressures across the nidus, thereby increasing the risk of hemorrhage.¹³ There are few studies that determine the nature of a bAVM following rupture.^{43,​ 50} However, once a bAVM with solely deep venous drainage has ruptured, the risk for further rupture remains increased, albeit slightly less than if unruptured (HR: 3.39–3.1; p  < 0.05).⁴³

24.9 Selected Papers on the Treatment of Ruptured bAVMs

●Lawton MT, Du R, Tran MN, et al. Effect of presenting hemorrhage on outcome after microsurgical resection of brain arteriovenous malformations. Neurosurgery 2005;56(3):485–493, discussion 485–493

●Aboukaïs R, Marinho P, Baroncini M, et al. Ruptured cerebral arteriovenous malformations: outcomes analysis after microsurgery. Clin Neurol Neurosurg 2015;138:137–142

●Ding D, Yen CP, Starke RM, Xu Z, Sheehan JP. Radiosurgery for ruptured intracranial arteriovenous malformations. J Neurosurg 2014;121(2):470–481

24.10 Treatment Options for Ruptured bAVM

Much of the initial management following ruptured bAVM stems from ICH management studies, which includes ICP control, blood pressure management to less than 140 mm Hg, external ventricular drainage for management of hydrocephalus/monitoring of ICP, reversal of coagulopathy, and monitoring in a neurological intensive care setting.^{56,​ 57,​ 58} Whether aggressive blood pressure targets are beneficial in ICH is debatable and several studies have shown varying results with no significant differences in mortality but potentially some benefit with functional outcomes.^{57,​ 59,​ 60,​ 61} Following initial diagnosis and management, subsequent goals are to decide on whether the bAVM is treatable and then the optimal timing for definitive treatment of the bAVM. Treatment options include conservative management, endovascular embolization, radiosurgery, microsurgery, or a combination of these strategies.

24.11 Surgery

Surgical treatment should be carried out for ruptured bAVMs in accordance with initial management of ICP and where large supratentorial hematoma (> 30 mL) or infratentorial hematoma (> 10 mL) is present, these should be evacuated initially with or without bAVM removal.⁶² Risk of rerupture, while initially increased following rupture, is still relatively low enough to delay treatment by several weeks or months. Irrespective of timing, surgery is dependent on previously described surgical grading systems, which are used for risk stratification following treatment. These help the neurosurgeon decide which ruptured bAVMs are suitable from a risk–benefit point of view for surgical resection. Grading systems include the Spetzler–Martin (SM), Spetzler–Ponce classification (SPC), and Lawton–Young (LY) supplementary grading systems.^{48,​ 63,​ 64,​ 65,​ 66} The SM and SPC gradings include size, venous drainage, and eloquent cortex involvement as proven predictors for operative outcome. The LY supplementary grading added on compactness, age, and rupture status. With rupture, the hematoma creates corridors that previously would require transection of cerebral tissue and therefore can improve surgical access to the bAVM.⁶⁷ In patients with already ruptured bAVMs and presurgery neurological deficits, patients have a decreased chance of developing new deficits. Comparing surgical resection in those who had ruptured bAVMs and nonruptured bAVMs in 232 patients, there were no significant differences in improved/unchanged outcomes (compared to preoperation) with surgery.⁶⁸

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