Radiosurgical Basics for the Treatment of Arteriovenous Malformations: Indications and Techniques

24 Radiosurgical Basics for the Treatment of Arteriovenous Malformations: Indications and Techniques

Edward A. Monaco III, Andrew Faramand, Ajay Niranjan, and L. Dade Lunsford

Abstract

Arteriovenous malformations have been treated by stereotactic radiosurgery from its beginnings. As with many pathologies, the indications and techniques for the treatment of arterioveous malformations by stereotactic radiosurgery have been refined over time with improvements in knowledge and technologies. The results of the controversial ARUBA trial have caused some to question the need to treat asymptomatic arteriovenous malformations. The purpose of this chapter is to introduce the indications for the treatment of arteriovenous malformations by stereotactic radiosurgery, explore the technique, and identify several of the areas in which this treatment has evolved.

Keywords: arteriovenous malformation, Gamma Knife, indications, stereotactic radiosurgery, techniques

Key Points

Stereotactic radiosurgery (SRS) is one of several treatment options for arteriovenous malformations (AVMs).
The indications for radiosurgery for AVMs include the following: surgically inaccessible or risky lesions, surgically low-risk lesions in medically infirm patients or those refusing surgery, limiting the risk of treating lesions in critical locations, treating residual nidus after previous failed treatments, and treating certain larger symptomatic lesions with no other treatment options.
The ARUBA (unruptured brain arteriovenous malformations) trial does not conclusively aid in decision-making regarding unruptured AVMs and treatment by SRS due, in part, to a limited follow-up period.
The Gamma Knife radiosurgical technique for AVM treatment involves stereotactic frame placement, image acquisition, target delineation, highly conformal dose planning, treatment execution, careful follow-up with serial magnetic resonance imaging studies, and confirmation of obliteration after the latency period with cerebral angiography.
Various alterations to the radiosurgical technique like dosestaged treatment of larger AVMs and the avoidance of preradiosurgical endovascular nidus embolization allow for safer and more efficacious treatment.

24.1 Introduction

Arteriovenous malformations (AVMs) are congenital vascular abnormalities comprising feeding arteries that are directly connected with draining veins without the interposition of a capillary bed to dampen pressure. The basic structure of an AVM includes a nidus, which is a vascular mass that shunts the blood from the feeding arteries to the draining veins. AVMs are rare, with an estimated incidence of 1 in 100,000 persons per year and prevalence estimated at 18 per 100,000.¹^,² The primary concern in a patient harboring an AVM is the risk of rupture and the potential for devastating neurological sequelae or even death. In the absence of hemorrhage, AVMs can lead to intractable vascular headache syndromes or seizure disorders. In the era of modern imaging, an increasing proportion of patients are having AVMs identified incidentally with minimal to no symptoms. Cerebral angiography remains the “gold standard” for the diagnosis of AVMs given it provides detailed information about the topography of an AVM, identifies the presence of intranidal or feeding artery aneurysms, and delineates the venous drainage pattern. The main goals of AVM treatment are to reduce or eliminate the risk of hemorrhage, ameliorate nonhemorrhagic symptoms, avoid future neurological deficits, and to do so in a fashion that is associated with the fewest complications.

More than 50% of individuals with AVMs present with hemorrhage, most commonly an intraparenchymal hemorrhage or a subarachnoid hemorrhage.³ Estimates on the overall risk of spontaneous AVM hemorrhage vary, but they typically range from around 2 to 4% per year and possibly less for unruptured AVMs.⁴^,⁵^,⁶^,⁷^,⁸^,⁹^,¹⁰^,¹¹ After an initial hemorrhage, the risk of rebleeding is increased and ranges between 6 and 15% during the first year.¹²^,¹³^,¹⁴^,¹⁵ Myriad factors have been associated with an increased risk of hemorrhage including small volume, seizures at presentation, the presence of deep venous drainage, the presence of intranidal or feeding artery aneurysms, and AVM location.¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰

Four treatment options are available to patients with diagnosed AVMs: observation, surgical resection, endovascular embolization, or stereotactic radiosurgery (SRS). The latter three can be used alone or in combination. Surgical resection is the “gold standard” treatment for AVMs. Complete resection of an AVM results in immediate elimination of hemorrhage risk that must be counterbalanced with the risks of surgery (i.e., general anesthetic risks, infection, stroke, etc.). Spetzler and Martin, among others, defined nidus size, pattern of venous drainage, and location within highly functional brain regions as critical features of an AVM that serve as outcome predictors for surgical resection at centers of excellence.²¹ These findings have been validated by various series and observational cohorts that indicate microsurgery is a safe and curative treatment strategy for low-grade AVMs.²²^,²³^,²⁴

Endovascular embolization has been advocated as a primary treatment strategy for AVMs.²⁵ However, the curative potential of embolization alone is generally considered to be low.²⁶^,²⁷^,²⁸^,²⁹ Embolization using a variety of coil, particulate, or glue methods may be used as an adjunct prior to microsurgery to induce flow reduction, limit surgical bleeding, and occlude difficult-to-reach or deep-seated arterial feeders.³⁰ Complication rates during embolization procedures vary widely with morbidity ranging from 1.4 to 50% and mortality varying from 1 to 4%.²⁵^,²⁶^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷ Given its lack of curative potential and its risk profile, a thoughtful evaluation of the role of embolization in each patient is necessary. One circumstance particularly suited to endovascular therapy may be treatment of aneurysms associated with AVMs.³⁸

The role of observation in patients harboring AVMs has recently come into sharper focus.³⁹^,⁴⁰ Although the role of treatment in the setting of ruptured AVMs is generally agreed upon, the management of unruptured AVMs is controversial. The risks of spontaneous hemorrhage must be compared to treatment-associated morbidity and mortality. The unruptured brain arteriovenous malformations (ARUBA) trial was the first randomized trial regarding the management of unruptured AVMs.³⁹ The study was undertaken to further elucidate the natural history of unruptured AVMs and the treatment-associated risks. An exhaustive treatise on the results of ARUBA and its flaws, as pointed out by its many detractors, is beyond the scope of this chapter. However, a brief mention is useful. In the study, 109 patients were randomized to medical management, while 114 were assigned to receive intervention, either embolization, SRS, microsurgery, or a combination thereof. The primary outcome measures were the occurrence of stroke or death. During a follow-up period of 33 months, 30.7% of the patients undergoing intervention suffered a stroke or died, compared to only 10.1% in the medical management arm. Three times as many patients in the intervention cohort were clinically impaired (modified Rankin score of 2 or higher), 46.2 versus 15.1%. The authors concluded that medical management was superior to medical management plus intervention for unruptured AVMs in this population followed for less than 3 years. Some of the more pointed criticisms include the following: few screened patients were eventually randomized, microsurgery was little used in the setting of low-grade AVMs for which it is particularly suited, endovascular embolization was used in a disproportionate number of patients despite its lack of curative potential and notable risks, and the follow-up period of 33 months was not sufficiently long to detect the benefits of intervention.⁴¹^,⁴² Outside the realm of unruptured AVMs, there are patients who are simply too medically ill, too aged, or possessing very difficult to treat AVMs for which treatment risks are too high and for whom observation may be the only reasonable strategy.⁴³

Radiation used to obliterate blood vessels in the brain as a treatment concept was first conceived of in the 1960s. Kjellberg advocated the proton Bragg peak stereotactic radiation approach in the 1970s and 1980s and more than 1,000 AVM patients were treated.⁴⁴^,⁴⁵ Only about 20% of patients experienced complete AVM obliteration using this technique. Lars Leksell treated the first patient harboring an AVM with the prototype Gamma Knife unit in Stockholm in 1970.⁴⁶ Target definition was based on the acquisition of biplane angiography performed during the procedure itself. Linear accelerator (LINAC) based technologies have been adapted for SRS for the treatment of AVMs at a number of centers worldwide.⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹ The emphasis of this chapter will be on the use of the Gamma Knife given that it is the device with which the authors are most familiar and on which the abundance of the literature is based. As of 2015, more than 100,000 patients harboring AVMs have been treated using the Gamma Knife worldwide.

SRS can be defined as the targeting of a lesion in an imaging-defined stereotactic coordinate system with focused, highly selective, sharp dose fall-off radiation. SRS has become a well-established treatment modality for AVMs with myriad published reports documenting its safety and efficacy. Radiosurgery causes AVM obliteration by inducing vascular injury and fibrosis that eventually leads to vessel thrombosis and occlusion.⁵² AVM obliteration rates vary widely and depend on the radiation dose administered and the volume of the AVM. The primary advantage of SRS for AVMs is risk avoidance, while the chief limitation is the latency period from the time of treatment to obliteration during which the risks of hemorrhage persist. This latency period is typically around 2 to 4 years, but can be longer. Patients who are not candidates for microsurgery due to advanced age, medical comorbidities, and surgical inaccessibility are often eligible for treatment with SRS. A complication unique to SRS treatment of AVMs is an adverse radiation effect (ARE). AREs can be transient or irreversible and can be defined as any new neurological symptom or sign that occurs after SRS in the absence of hemorrhage.⁵³ AREs reportedly occur in 3 to 11% of patients after SRS for AVMs.⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰

AVM treatment should be carefully tailored to each individual patient on the basis of his or her lesion, medical comorbidities, the risks and benefits of available options, and patient desires and expectations. A thorough understanding of the indications and techniques of AVM treatment greatly enhances the potential for patients to have excellent outcomes with minimal toxicity. The first objective of this chapter is to specifically delineate the indications for treatment of AVMs by SRS. The second objective is to explore various features of the radiosurgical technique.

24.2 Materials and Methods

A literature search of PubMed was performed to identify the relevant published literature regarding this topic. Institution experience from the University of Pittsburgh is included.

24.3 Results

24.3.1 Indications for Stereotactic Radiosurgery

In general, treatment of an AVM is indicated when the risks of the natural history are greater than the risks of treatment or when nonhemorrhagic symptoms are sufficiently incapacitating that accepting the risks of treatment is felt to be worth enduring to eliminate them (► Table 24.1).

Table 24.1 Current roles for radiosurgical treatment of arteriovenous malformations (AVMs)

Indications for stereotactic radiosurgery treatment of AVMs
Deep-seated AVMs without surgical options
Small/medium sized AVMs
AVMs in critical locations with high surgical risk
Residual AVMs left after prior management
Select larger, symptomatic AVMs without treatment alternatives

The following factors are considered when determining a patient’s suitability for SRS: age, medical comorbidities, history of AVM rupture, prior management, AVM volume and morphology, AVM location, presenting symptoms, angioarchitecture (i.e., diffuse vs. compact nidus), surgical candidacy, and the existence of feeding artery or intranidal aneurysms.

One of the primary indications for SRS is when an AVM is not easily surgically accessible or its functional location has resulted in it being characterized a too high a risk for surgery.²¹ For instance, AVMs within the brainstem are a particularly challenging entity wherein the often unacceptably high risks of surgery make SRS an attractive alternative.⁶¹ In contrast, microsurgical resection for low-grade AVMs is the “gold standard,” but SRS can be a gradually effective and relatively safe alternative for patients who are not candidates for surgery due to medical comorbidities or have declined it.⁶²

SRS has a meaningful role in the treatment of residual AVM nidi that have been left after previous treatments. A meaningful number of patients reported on in radiosurgical series underwent prior attempts at microsurgical cure or endovascular embolization. Often in these cases, it is felt at the time of surgery that a remnant must be left to avoid harming a patient. One of the few published reports on the role of SRS for partially resected AVMs is by Ding et al.⁶³ In this case-matched analysis, no differences in the rates of obliteration and postradiosurgical hemorrhage were found between previously resected and unresected AVMs. Endovascular embolization may have been utilized in hopes of diminishing the nidus size, decreasing overall AVM flow, and potentially reducing the risk of subsequent hemorrhage. There are little data to support this hypothesis. SRS can also be repeated when it fails to achieve complete AVM obliteration.⁶⁴

Finally, SRS is indicated for select patients with larger, symptomatic AVMs for whom no other treatment options are available. With the use of volume and dose staging, very challenging AVMs have a hope of meaningful rates of complete obliteration.

An important question regarding the indications for SRS is, How have the results of the ARUBA trial changed its indications for the treatment of unruptured AVMs? Because of its limited follow-up period of 33 months, and the latency of the treatment effect of SRS, the ARUBA study does not seem to aid in decision-making regarding SRS for AVMs at all. Several groups have specifically evaluated outcomes after SRS in ARUBA-eligible patients to offer more data. Ding et al reported on 509 ARUBA-eligible patients treated by SRS in a multicentered retrospective study with a mean follow-up period of 86 months.⁴² This study suggests that on the basis of post-SRS hemorrhage rates and complications, a follow-up period of 15 to 20 years would be required to realize the benefits of SRS over conservative management. Using the same eligibility criteria as the ARUBA trial, Pollock et al retrospectively observed that the risk of stroke or death in 174 patients treated by SRS was 2% per year for the first 5 years after treatment and 0.2% thereafter.⁶⁵ They suggest that patients harboring small-volume AVMs may benefit from SRS when compared to the natural history over a period of 5 to 10 years. The lack of meaningful conclusions regarding SRS via the ARUBA trial, taken together with these data, supports a role for the treatment of unruptured AVMs in relatively young patients.

24.3.2 Gamma Knife Stereotactic Radiosurgery Technique

SRS with the Gamma Knife is a collaboration between a neurosurgeon, radiation oncologist, and medical physicist, and involves a multistep process (► Table 24.2). Under most circumstances, it is performed on an outpatient basis. We routinely use anticonvulsant therapy in patients harboring lobar AVMs in order to reduce the risk of periprocedural seizures. Traditionally, the procedure begins with the application of an imaging compatible stereotactic head frame to the patient. This is performed after the administration of local anesthetic to the scalp and often supplemented by intravenous sedation (fentanyl and midazolam). Children under the age of 12, or those who cannot tolerate the procedure otherwise, are often administered general endotracheal anesthesia. Prior to the introduction of the newest Gamma Knife, the Icon, the procedure was only very rarely performed in the absence of a head frame. The Icon device allows for mask-based immobilization when used in conjunction with the acquisition of stereotactic cone-beam computed tomography (CT) and real-time image-guidance movement tracking. Mask-based immobilization also allows for noninvasive fractionated or multisession treatments, although there are no data yet published regarding this technique.

Table 24.2 Stereotypical radiosurgical treatment methods with the Gamma Knife

The steps of a typical Gamma Knife SRS procedure
Stereotactic head frame placement
Image acquisition (fine-cut axial contrasted and T2 MRI, stereotactic biplane angiography) and target definition
Dose selection and treatment planning
Treatment administration
Follow-up with serial MRI scans
Confirmation of obliteration by cerebral angiography