Multimodal/Combined Therapy: Goals and Outcomes

Introduction

An arteriovenous malformation (AVM) is an abnormal proliferation of blood vessels that results in a direct connection between arteries and veins without intervening capillaries. The nidus of an AVM is the tangle of these direct connections through which blood is shunted from artery to vein. The primary clinical concern for patients with intracranial AVMs (iAVMs) is the risk of rupture and resulting hemorrhagic stroke, which has been estimated at approximately 2%–4% per year for patients with unruptured iAVMs, and the primary purpose of treatment is to reduce or eliminate this risk. Choosing the appropriate iAVM management for an individual patient involves weighing the risks associated with treatment against the risks associated with continued observation.

In determining whether to treat an unruptured iAVM—and which form of treatment to opt for—morphological and anatomical characteristics of the lesion as well as patient-specific characteristics must be taken into account, and the patient’s lifetime risk of AVM-associated hemorrhage must be balanced against the risks associated with treatment. A large nidus, the presence of intranidal aneurysms, deep or infratentorial location, and deep venous drainage/venous outflow obstruction have been shown to increase the risk of hemorrhage and therefore are factors that would shift the balance toward intervention, as opposed to observation. However, these same factors may increase the risk of intervention.

Many scales have been designed to quantify the risks associated with treating iAVMs and to stratify patients into “high-risk” and “low-risk” candidates. Though these grading schemes are discussed in greater detail in Chapter 8 , a discussion about combined therapies warrants a reminder of the features of iAVMs that confer greater morbidity. The best known of these schemes is the Spetzler-Martin grading system, which was developed to estimate the risk involved with microsurgical resection. It is a five-point scale that includes size of nidus (small [< 3 cm] = 1 point, medium [3–6 cm] = 2 points, large [> 6 cm] = 3 points), eloquence of adjacent brain (noneloquent = 0 points, eloquent = 1 point), and pattern of venous drainage (superficial veins only = 0 points, deep veins = 1 point). The more points, the higher the risk of deficit or rupture associated with surgery.

Decisions about treating an unruptured iAVM are influenced by the modality or therapy offered: radiosurgery, embolization, microsurgical resection, or any combination of the three (referred to as multimodality therapy). Stereotactic radiosurgery (SRS) delivers high-dose, focused radiation to the AVM nidus to induce endothelial and sclerotic changes, leading to eventual thrombosis of the AVM. When used as a monotherapy, the goal is obliteration of the nidus. When SRS is used as part of a combined therapy, often an area of the nidus that was not obliterated with embolization or resection will be targeted. Microsurgical resection is ideal for compact AVMs that are located in a surgically accessible area of the brain. Advantages of microsurgery include the ability to immediately eliminate hemorrhage risk and high rates of nidus obliteration and long-term effectiveness. Embolization is often used as an adjuvant to radiosurgery and microsurgical resection, although in select cases, it can be used as a primary method of obliteration of the AVM nidus. Permutations of any of the above strategies have been used as efficacious ways of treating AVMs, and in this chapter, we will discuss the goals and outcomes of combination therapy.

Embolization and Radiosurgery

Embolization prior to SRS is useful to optimize the characteristics of an iAVM for radiosurgical treatment. SRS is utilized when microsurgical resection is not possible due to the AVM’s location, size, or feeding vessels or medical comorbidities that would preclude a patient from undergoing an operation. It is indicated for small AVMs (< 3 cm in maximum diameter and < 12 cm ³ in volume) that are located in eloquent and/or deep regions of the brain. Embolization can reduce the nidus volume prior to SRS. Targeted embolization is a new technique employed to specifically target high-risk features of an AVM, including arteriovenous fistulas and intranidal and perinidal aneurysms.

In meta-analyses of outcome studies of SRS for the treatment of iAVMs with and without prior embolization, the AVM obliteration rate was significantly lower in the population of patients who received embolization prior to SRS. A major limitation to these studies, however, is the lack of accounting for differences in the characteristics of AVMs treated with embolization prior to SRS vs SRS alone. Additional theories for the lower obliteration rates associated with pre-SRS embolization include delayed recanalization of embolized portions of the AVM and difficulty in accurately targeting residual lesion due to radiopaque embolic material. As of this writing, there are no published results from any randomized control trial studying the outcome of embolization prior to SRS, and the true effectiveness of this approach is unclear. One objective of the TOBAS (Treatment of Brain AVMs) clinical trial ( clinicaltrials.gov identifier NCT02098252) is to determine whether presurgical or preradiosurgery embolization of AVMs can increase obliteration and decrease treatment failures with an acceptable risk.

Multiple agents have been utilized in the embolization of AVMs. Currently, N-butyl cyanoacrylate (NBCA), ethylene-vinyl alcohol copolymer (Onyx; Medtronic, Minneapolis, MN), and polyvinyl alcohol (PVA) particles are used during embolization. In a clinical trial assessing outcomes of treatment with Onyx vs NBCA, there was no significant difference in the outcome (> 50% AVM volume reduction), resection time, or blood loss. Both NBCA and Onyx are permanent embolic agents, although recanalization can occur. One advantage to Onyx is that it solidifies slowly, reducing the risk of premature polymerization within the microcatheter and allowing for repeated injection and more distal embolization.